Pelvic Inflammatory Disease

Infectious Disease MONDO:0000922 Pathograph 20 Show in embeddings browser Female reproductive system disorder Inflammatory disease Bacterial infectious disease

Pelvic inflammatory disease is inflammation of the female upper genital tract that follows ascent of organisms from the cervix and vagina into the endometrium, fallopian tubes, and adjacent pelvic structures. Endometritis, salpingitis, tubo-ovarian abscess and pelvic peritonitis are points on one spectrum rather than separate diseases. Two features make PID mechanistically distinctive. First, the damage that matters clinically is inflicted by the host response, not by the organism: gonococcal cell-wall fragments and chlamydial antigens provoke a TNF-driven, neutrophil-dominant reaction that sloughs the multiciliated tubal epithelium, and the resulting fibrosis and luminal occlusion are irreversible. Second, the disease is frequently silent — a large share of tubal factor infertility arises in women who never had a symptomatic episode — so the interval between infection and diagnosis, rather than the organism's identity, is the strongest modifiable determinant of outcome. Neisseria gonorrhoeae and Chlamydia trachomatis are the classical pathogens, but fewer than half of contemporary cases yield either; Mycoplasma genitalium and the anaerobic consortium of bacterial vaginosis account for a substantial further fraction, and this etiological shift is not fully covered by the recommended regimen.

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Discussions and Knowledge Gaps

Why does treating gonococcal, chlamydial and bacterial-vaginosis infection fail to restore fertility in women who already have subclinical endometritis, and what would an intervention that does work have to target?

KNOWLEDGE GAP OPEN pid_subclinical_treatment_failure

Attached to

pathophysiology#Subclinical Upper Genital Tract Inflammation pathophysiology#Tubal Factor Infertility

This is the most consequential gap in the entry, and it is awkward for the whole prevention model. In a prospective cohort, women who had biopsy-defined subclinical PID at enrollment had a 40% lower subsequent pregnancy incidence even though they received treatment for their gonococcal, chlamydial or bacterial-vaginosis infection — while women with those same infections but without subclinical PID were not at increased risk. The dividing line is therefore the presence of upper tract inflammation, not the presence of the organism, and antimicrobial therapy directed at the organism does not undo it. Either the damage is already fixed by the time endometritis is detectable, or the inflammation persists after the organism is cleared. The two possibilities imply completely different interventions — earlier detection versus anti-inflammatory adjunctive therapy — and nothing in the current evidence distinguishes them.

Proposed experiments

Serial endometrial sampling after treatment of subclinical PID

prospective cohort with serial endometrial biopsy

pid_endometritis_resolution_cohort

Follow women with biopsy-confirmed subclinical endometritis through and after standard antimicrobial therapy with repeat endometrial biopsy and organism testing, and relate persistence of histologic inflammation (as opposed to persistence of the organism) to subsequent tubal patency and fertility. A dissociation — organism cleared, inflammation persisting, fertility reduced — would identify the residual inflammation as the target and justify testing an anti-inflammatory adjunct.

Would support

pathophysiology#Subclinical Upper Genital Tract Inflammation

Show evidence (3 references)

PMID:22678036 SUPPORT Human Clinical

"Subclinical PID decreases subsequent fertility despite provision of treatment for sexually transmitted diseases."

States the failure of organism-directed treatment to prevent the fertility loss.

PMID:22678036 SUPPORT Human Clinical

"Women with Neisseria gonorrhoeae or Chlamydia trachomatis, in the absence of subclinical PID, were not at increased risk for infertility."

Establishes that upper tract inflammation, rather than the organism, is the discriminating variable — the observation that makes this a mechanistic gap rather than a treatment-adherence problem.

PMID:34292926 SUPPORT Human Clinical

"The optimal treatment regimen and long-term outcome of early treatment of women with subclinical PID are unknown."

The CDC guideline states this gap in its own words, so the discussion rests on a quoted source rather than on inference from the cohort data alone.

If fewer than half of PID cases involve gonorrhoea or chlamydia, is a regimen designed around those two organisms still the right one?

OPEN QUESTION OPEN pid_etiology_regimen_mismatch

Attached to

pathophysiology#Lower Genital Tract Infection and Cervical Colonization pathophysiology#Loss of Vaginal Lactobacillus Dominance

The recommended regimen was built around N. gonorrhoeae and C. trachomatis, but contemporary series find neither organism in more than half of diagnosed cases, with M. genitalium, respiratory pathogens and the bacterial-vaginosis consortium accounting for a substantial share. The metronidazole trial is the first piece of that gap to be closed with randomised evidence, and it closed it in the direction of the anaerobes. The M. genitalium share remains uncovered: a PEACH substudy showed that cefoxitin plus doxycycline does not eradicate endometrial M. genitalium and that carriage predicted short-term treatment failure. Whether that translates into a change of regimen depends on evidence that does not yet exist, since no trial has shown that treating M. genitalium prevents PID or its sequelae.

Show evidence (3 references)

PMID:34396398 SUPPORT Human Clinical

"Recent studies of women with PID have reported that fewer than half of women receiving a diagnosis of PID have gonococcal or chlamydial infection, while Mycoplasma genitalium, respiratory pathogens, and the constellation of bacteria associated with bacterial vaginosis may account for a..."

Quantifies the mismatch between the regimen's design and the observed etiology.

PMID:18445635 SUPPORT Human Clinical

"Cefoxitin and doxycycline, a Centers for Disease Control and Prevention recommended PID treatment regimen, is ineffective for the treatment of M genitalium upper genital tract infection."

Demonstrates the specific coverage failure for M. genitalium.

PMID:18192788 SUPPORT Human Clinical

"PCR studies have demonstrated that M. genitalium is associated with clinically suspected pelvic inflammatory disease, acute endometritis, and adnexitis, independent of gonococcal and chlamydial infection."

Establishes that the M. genitalium association is independent of the two classical organisms, so it is not explained by co-infection.

What mechanism connects a resolved episode of upper genital tract inflammation to persistent pelvic pain years later?

KNOWLEDGE GAP OPEN pid_chronic_pain_mechanism

Attached to

pathophysiology#Chronic Pelvic Pain

Chronic pelvic pain is one of the three canonical sequelae of PID and is the most common long-term complaint, yet unlike infertility and ectopic pregnancy it has no structural correlate in this pathograph. Post-inflammatory adhesions are the usual explanation, but the pain frequently persists in women whose acute infection was treated and cleared, and no cited source here demonstrates the adhesion-to-pain step. The edge from tubal fibrosis to chronic pain in this entry is deliberately typed INDIRECT_UNKNOWN_INTERMEDIATES for that reason: naming adhesions as the mechanism would assert more than the cited literature supports.

Show evidence (1 reference)

PMID:18445635 SUPPORT Human Clinical

"Rates of sequelae, including infertility (22%), recurrent PID (31%) and chronic pelvic pain (42%), were high among women testing positive for endometrial M genitalium at baseline."

Documents the high rate of chronic pelvic pain in a treated trial cohort, showing the sequela is common despite therapy.

⚙

Pathophysiology

Lower Genital Tract Infection and Cervical Colonization

Establishment of Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium or bacterial-vaginosis-associated anaerobes at the endocervix. This is the reservoir from which the upper tract is seeded, and it is where the disease is interruptible: detecting and treating cervical infection at this stage prevents PID, whereas nothing downstream reverses tubal damage once it has occurred. Most cervical infection is asymptomatic, which is why the node is usually crossed unobserved.

biological process involved in interaction with host GO:0051701

uterine cervix UBERON:0000002

Downstream

Ascension to the Upper Genital Tract Organisms established at the cervix move upward into the endometrial cavity and fallopian tubes.

Show evidence (2 references)

PMID:34396413 SUPPORT Human Clinical

"Neisseria gonorrhoeae and Chlamydia trachomatis are the 2 most commonly recognized PID pathogens."

Names the two classical organisms colonizing the lower tract before ascent.

PMID:34396398 SUPPORT Human Clinical

Establishes that the causative organism pool is broader than the two classical pathogens, which is why this node is not named for a single species.

Loss of Vaginal Lactobacillus Dominance

Replacement of a lactobacillus-dominated vaginal community by a diverse anaerobic consortium (Gardnerella vaginalis, Megasphaera, Atopobium). This is the bacterial vaginosis arm of PID: it supplies organisms that can themselves ascend, and it is the reason anaerobic coverage is part of the regimen. It is curated as a parallel entry route rather than as a step in the sexually transmitted chain, because it does not require acquisition of a classical STI pathogen.

biological process involved in interaction with host GO:0051701 ⚠ ABNORMAL

vagina UBERON:0000996

Downstream

Ascension to the Upper Genital Tract Anaerobes from the disturbed vaginal community reach the endometrium. The edge is typed UNKNOWN deliberately: the association with endometritis and PID is well documented, but the review that states it also states that the mechanism of ascent is unclear.

Show evidence (2 references)

PMID:33091407 SUPPORT Human Clinical

"Bacterial vaginosis is characterized by a lower prevalence of lactobacilli and a higher prevalence of anaerobic bacteria, including Gardnerella vaginalis, Megasphaera spp., and Atopobium vaginae."

Defines the microbial shift this node represents.

PMID:32052831 SUPPORT Human Clinical

"Anaerobic organisms are important pathogens in acute pelvic inflammatory disease (PID)."

Independent trial-based statement that anaerobes are genuine PID pathogens, not bystanders, supporting this as a causal node.

Ascension to the Upper Genital Tract

Arrival of organisms in the endometrial cavity and fallopian tubes, producing the endometritis-salpingitis spectrum that is PID. Because the endometrium and tube are contiguous, the same event is named endometritis, salpingitis, tubo-ovarian abscess or pelvic peritonitis depending on how far it has extended, and these are not separate diseases.

fallopian tube multiciliated epithelial cell CL:4030007

inflammatory response GO:0006954 ↑ INCREASED

endometrium UBERON:0001295 fallopian tube UBERON:0003889

Downstream

Intracellular Survival and Innate Immune Evasion Organisms that reach the upper tract invade and persist within tubal epithelium and recruited phagocytes.

Neutrophil-Dominant Innate Inflammation with Dampened T-Cell Activation Upper tract infection provokes an innate, myeloid-dominated inflammatory response in the endometrium.

Tubo-ovarian Abscess and Pelvic Peritonitis Continued spread beyond the tubal lumen to the ovary and peritoneal cavity.

Show evidence (2 references)

PMID:34396398 SUPPORT Human Clinical

"Endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis are all on the spectrum of inflammatory processes comprising PID."

States that the named clinical entities are one spectrum, which is what this node represents.

PMID:25592078 SUPPORT Human Clinical

"If infections are either not resolved or left untreated, chlamydia can ascend to the upper FGT and infect the fallopian tubes (FTs) causing salpingitis that may lead to functional damage of the FTs and tubal factor infertility (TFI)."

Traces the chain from untreated lower tract infection through ascent to salpingitis and functional tubal damage.

Intracellular Survival and Innate Immune Evasion

Both classical PID pathogens persist inside host epithelial cells and neutrophils and actively subvert the innate response, which is why the infection is chronic and why the therapeutic requirement is for an agent that reaches the intracellular compartment. This is the lifestyle-gating step: it constrains which drugs can work, independently of any organism's in vitro susceptibility.

fallopian tube multiciliated epithelial cell CL:4030007 neutrophil CL:0000775

biological process involved in interaction with host GO:0051701

Downstream

Requirement for a Cell-Penetrant Antimicrobial Because the organisms sit inside host cells, effective therapy is restricted to agents that accumulate intracellularly.

Show evidence (3 references)

PMID:34396413 SUPPORT Human Clinical

"Their ability to survive within host epithelial cells and neutrophils highlights a need for T-cell-mediated production of interferon γ in protection."

States the intracellular niche in the two classical PID pathogens, which is the module's gating condition.

PMID:34396413 SUPPORT Human Clinical

"Both pathogens exert multiple mechanisms of immune evasion that benefit themselves and each other at the expense of the host."

Supports the active immune-evasion component of this node, curated separately from the intracellular-niche claim because it is a distinct assertion.

PMID:18611821 SUPPORT Other

"The intracellular location of some microorganisms allow them to resist antibiotics with poor ability to penetrate eukaryotic cell membranes, such as the beta-lactam compounds."

The general principle the module encodes, cited here to justify the conformance rather than to assert anything PID-specific. Evidence source OTHER as this is a review.

Requirement for a Cell-Penetrant Antimicrobial

The therapeutic consequence of the intracellular niche: efficacy tracks the intracellular concentration achieved rather than the in vitro MIC, so doxycycline rather than the cephalosporin is the component of the PID regimen that addresses chlamydial upper tract infection. This node exists to carry that constraint explicitly; it is why every recommended PID regimen pairs a cephalosporin with a tetracycline instead of escalating the cephalosporin.

response to antibiotic GO:0046677

Show evidence (2 references)

PMID:28639230 SUPPORT Other

"Therapeutic efficacy against intracellular pathogens has been correlated mainly with the intracellular concentrations achieved by the different antimicrobial agents."

The pharmacokinetic principle the node encodes. Evidence source OTHER as this is a review.

PMID:31524362 SUPPORT Human Clinical

"Mild to moderate disease can be treated in an outpatient setting with a single intramuscular injection of a recommended cephalosporin followed by oral doxycycline for 14 days."

Shows the recommended regimen pairing a cephalosporin with the cell-penetrant tetracycline, which is the clinical expression of this requirement.

Neutrophil-Dominant Innate Inflammation with Dampened T-Cell Activation

The host response that actually causes the damage. Endometrial tissue from women with histologically confirmed PID shows activation of myeloid, cell death and innate inflammatory programmes together with suppression of T-cell activation — an inflammatory response that is intense but non-protective, which is consistent with the absence of durable immunity after natural infection and with the high rate of reinfection.

neutrophil CL:0000775 CD4-positive, alpha-beta T cell CL:0000624 ↓ DECREASED

neutrophil chemotaxis GO:0030593 ↑ INCREASED tumor necrosis factor production GO:0032640 ↑ INCREASED

endometrium UBERON:0001295

Downstream

TNF-Mediated Sloughing of Ciliated Tubal Epithelium Mucosal TNF-alpha produced during infection is the proximate mediator of ciliated cell loss.

Chlamydial HSP60-Directed Immunopathology In chlamydial disease the adaptive arm of the same response is directed at cHSP60 released from infected cells.

Show evidence (2 references)

PMID:34396413 SUPPORT Human Clinical

"A study of women with N. gonorrhoeae- and/or C. trachomatis-induced PID with histologic endometritis revealed activation of myeloid cell, cell death, and innate inflammatory pathways in conjunction with dampening of T-cell activation pathways."

Direct human tissue-level evidence for both halves of this node: innate activation and suppressed T-cell activation.

PMID:25592078 SUPPORT Human Clinical

"Chlamydial pathogenesis of irreversible and permanent tubal damage is a consequence of innate and adaptive host immune responses to ongoing or repeated infections."

States explicitly that the permanent damage is caused by the host response, which is the organising claim of this node.

TNF-Mediated Sloughing of Ciliated Tubal Epithelium

Detachment and loss of the multiciliated cells lining the tubal mucosa, the lesion that converts a transient infection into permanent transport failure. The classical human fallopian tube organ culture work established that this is not direct bacterial cytotoxicity: purified gonococcal peptidoglycan monomers reproduce the damage in the absence of live organisms, and recombinant TNF-alpha alone is sufficient. Because the ciliated epithelium does not regenerate its function, this node is the point at which the disease becomes irreversible.

fallopian tube multiciliated epithelial cell CL:4030007 ↓ DECREASED

cilium movement GO:0003341 ↓ DECREASED

fallopian tube UBERON:0003889

Downstream

Tubal Fibrosis and Luminal Occlusion Repeated or sustained epithelial destruction is followed by scarring of the tube. The edge is typed INDIRECT_UNKNOWN_INTERMEDIATES because the human evidence links the inflammatory response to fibrosis and occlusion as an outcome, without identifying the mesenchymal steps in between.

Tubal Factor Infertility Loss of ciliary transport, together with subsequent scarring, prevents normal gamete and embryo transport.

Show evidence (2 references)

PMID:10100774 SUPPORT In Vitro

"Gonococcal infection of human fallopian tube mucosa in organ culture results in the sloughing of ciliated epithelial cells from the mucosa."

Establishes the lesion itself in the human ex vivo model.

PMID:6425421 SUPPORT In Vitro

"The damage produced by either of these peptidoglycan monomers resulted in sloughing of ciliated cells from the mucosa and resembled the damage observed in active gonococcal infection"

Shows that a purified bacterial cell-wall fragment reproduces the lesion without live organisms, which is the evidence that the damage is host-mediated rather than an effect of bacterial invasion.

Chlamydial HSP60-Directed Immunopathology

The chlamydia-specific arm of the immunopathology. Chlamydial heat shock protein 60, released when infected cells lyse, is recognised by T-cell clones recoverable from inflamed salpingeal tissue of women with tubal factor infertility, and drives the proinflammatory response that ends in fibrosis. Curated as a separate node from the generic innate response because the antigen, the effector cell type and the clinical correlate are all specific to chlamydia.

CD4-positive, alpha-beta T cell CL:0000624 ↑ INCREASED

inflammatory response GO:0006954 ↑ INCREASED

fallopian tube UBERON:0003889

Downstream

Tubal Fibrosis and Luminal Occlusion cHSP60-driven inflammation is the proposed route to fibrosis and occlusion of the tubal lumen in chlamydial disease.

Show evidence (2 references)

PMID:11779608 SUPPORT In Vitro

"Seventy-seven (34%) of the 229 T-lymphocyte clones recognized C. trachomatis and C. pneumoniae elementary bodies as target antigens. One-third of these Chlamydia genus-specific T-lymphocyte clones further recognized CHSP60 as the target antigen."

Recovery and cloning of cHSP60-reactive T cells from salpingeal tissue of women with tubal factor infertility. Classified IN_VITRO because the measurement is on cultured T-lymphocyte clones, although the tissue was human surgical material.

PMID:25592078 SUPPORT Human Clinical

"When released from infected cells, cHSP60 can induce proinflammatory immune responses that may functionally impair the FTs leading to fibrosis and luminal occlusion."

States the cHSP60 release, proinflammatory response and fibrotic endpoint that this node encodes.

Tubal Fibrosis and Luminal Occlusion

Replacement of damaged tubal mucosa by scar, with adhesion formation and narrowing or closure of the lumen; hydrosalpinx is its imaged form. Matrix metalloproteinase regulation of the extracellular matrix is implicated. This is the structural lesion that all the downstream reproductive consequences share.

fibroblast CL:0000057

extracellular matrix organization GO:0030198 ↕ DYSREGULATED collagen fibril organization GO:0030199 ↑ INCREASED

fallopian tube UBERON:0003889

Downstream

Tubal Factor Infertility An occluded or scarred tube cannot transport gametes or the embryo.

Ectopic Implantation A partially patent, scarred tube retains the embryo rather than transporting it, permitting tubal implantation.

Chronic Pelvic Pain Post-inflammatory adhesive disease is the usual explanation offered for persistent pain after PID, but the mechanism connecting the structural lesion to the pain syndrome is not established; the edge is typed accordingly.

Show evidence (2 references)

PMID:25592078 SUPPORT Human Clinical

"When released from infected cells, cHSP60 can induce proinflammatory immune responses that may functionally impair the FTs leading to fibrosis and luminal occlusion."

Names fibrosis and luminal occlusion as the endpoint of the tubal inflammatory response.

PMID:25592078 SUPPORT Human Clinical

"The extracellular matrix that is regulated by metalloproteinases may also be modified by chlamydial infections of the FGT."

Supports the matrix-remodelling annotation on this node. Marked PARTIAL because the review states it as a possibility rather than an established finding, which is also why no fibrotic_response module conformance is claimed here.

Tubo-ovarian Abscess and Pelvic Peritonitis

Extension of infection beyond the tubal lumen into a walled-off adnexal collection and onto the peritoneal surface. This is the acute-severity branch: it is the branch that requires hospitalization and, when medical therapy fails, drainage or surgery, and it is what makes PID an occasionally surgical disease rather than a purely outpatient one.

inflammatory response GO:0006954 ↑ INCREASED neutrophil chemotaxis GO:0030593 ↑ INCREASED

ovary UBERON:0000992 peritoneum UBERON:0002358

Show evidence (1 reference)

PMID:31524362 SUPPORT Human Clinical

"Hospitalization for parenteral antibiotics is recommended in patients who are pregnant or severely ill, in whom outpatient treatment has failed, those with tubo-ovarian abscess, or if surgical emergencies cannot be excluded."

Establishes tubo-ovarian abscess as the branch that changes management, which is why it is modelled as its own node.

Subclinical Upper Genital Tract Inflammation

Histologic endometritis without a symptomatic PID episode. This is the most consequential feature of the disease for the knowledge base, because it breaks the assumption that treating the diagnosable disease prevents the sequelae: in a prospective cohort, women with biopsy-defined subclinical PID had a 40% lower incidence of pregnancy despite receiving treatment for their gonococcal, chlamydial or bacterial-vaginosis infection, while women with those infections but without subclinical PID were not at increased risk. Most tubal factor infertility therefore arises along a route that current care does not intercept.

inflammatory response GO:0006954 ↑ INCREASED

endometrium UBERON:0001295

Downstream

Tubal Factor Infertility Subclinical endometritis reduces subsequent fertility even when the associated lower tract infection is treated. The intervening tubal events are not observed in these women, since the cohort endpoint is fertility rather than tubal morphology.

Show evidence (2 references)

PMID:22678036 SUPPORT Human Clinical

"Women with subclinical PID diagnosed at enrollment had a 40% reduced incidence of pregnancy compared with women without subclinical PID (hazard ratio 0.6, 95% confidence interval 0.4-0.8)."

Prospective cohort quantifying the fertility cost of subclinical endometritis.

PMID:34396413 SUPPORT Human Clinical

"Since most women with tubal factor infertility have no history of symptomatic PID, damage to the fallopian tubes may occur with subclinical infections"

Independent statement that the majority of tubal factor infertility follows subclinical rather than symptomatic disease.

Tubal Factor Infertility

Inability to conceive attributable to tubal damage. Risk rises with the number and severity of PID episodes, which is the clearest available evidence that the lesion is cumulative rather than all-or-none.

fallopian tube UBERON:0003889

Show evidence (1 reference)

PMID:1411832 SUPPORT Human Clinical

"Tubal factor infertility after PID was associated with number and severity of PID episodes."

Establishes the dose-response with episode count and severity.

Ectopic Implantation

Implantation of the conceptus in the damaged tube. The Westrom cohort puts the ectopic rate for the first pregnancy after laparoscopically verified PID at 9.1% against 1.4% in laparoscopy-normal controls, an approximately sixfold excess. This node is the point of contact between this entry and the separate Ectopic Pregnancy entry, which models the implantation event itself.

fallopian tube UBERON:0003889

Show evidence (1 reference)

PMID:1411832 SUPPORT Human Clinical

"The ectopic pregnancy rate for first pregnancy after index laparoscopy was 9.1% among the patients and 1.4% among control subjects."

Quantifies the ectopic pregnancy excess after verified PID against a laparoscopically normal comparison group.

Chronic Pelvic Pain

Persistent pelvic pain after the acute episode, the most common long-term complaint and the one least well explained mechanistically. It is frequent enough after PID to be a defining sequela — 42% among women with endometrial M. genitalium in the PEACH substudy — yet no node in this pathograph accounts for it in mechanistic terms, which is recorded as a knowledge gap rather than papered over.

Show evidence (2 references)

PMID:31524362 SUPPORT Human Clinical

"Untreated PID can lead to chronic pelvic pain, infertility, ectopic pregnancy, and intra-abdominal infections."

Names chronic pelvic pain among the established sequelae of untreated PID.

PMID:18445635 SUPPORT Human Clinical

"Rates of sequelae, including infertility (22%), recurrent PID (31%) and chronic pelvic pain (42%), were high among women testing positive for endometrial M genitalium at baseline."

Quantifies the sequela rates in a treated PID trial population.

Delayed Presentation and Treatment

The interval between symptom onset and effective therapy, curated as a node rather than as context because it is the strongest modifiable determinant of outcome in this disease and because it acts on the pathograph — it lengthens the period during which the inflammatory lesion accumulates. Delay is driven by the nonspecific clinical picture and by the absence of any validated noninvasive diagnostic test.

Downstream

Tubal Fibrosis and Luminal Occlusion Delay prolongs the inflammatory phase, allowing more tubal damage to accumulate before it is arrested.

Show evidence (2 references)

PMID:8498436 SUPPORT Human Clinical

"Women who delayed seeking care for pelvic inflammatory disease were three times more likely to experience infertility or ectopic pregnancy than women who sought care promptly"

Quantifies the effect of delay on the two principal reproductive sequelae.

PMID:34396398 SUPPORT Human Clinical

"The clinical diagnosis of PID is nonspecific, creating an urgent need to develop noninvasive tests to diagnose PID."

Identifies the diagnostic imprecision that produces the delay.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Digestive 1

Peritonitis HP:0002586

Show evidence (1 reference)

PMID:34396398 SUPPORT Human Clinical

"Endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis are all on the spectrum of inflammatory processes comprising PID."

Places pelvic peritonitis within the PID spectrum.

Genitourinary 2

Female infertility OCCASIONAL HP:0008222

Show evidence (1 reference)

PMID:1411832 SUPPORT Human Clinical

"A total of 141 (10.8%) of the patients and 0 (0%) of the control subjects had confirmed tubal factor infertility"

10.8% confirmed tubal factor infertility among women with laparoscopically verified PID, which falls in the OCCASIONAL band (5-29%).

Dyspareunia HP:0030016

Show evidence (1 reference)

PMID:34292926 SUPPORT Human Clinical

"the patient or the health care provider do not recognize the implications of mild or nonspecific symptoms or signs (e.g., abnormal bleeding, dyspareunia, and vaginal discharge)."

Lists dyspareunia among the presenting symptoms of PID. No frequency band is assigned because the guideline characterizes these as mild or nonspecific without quantifying them.

Metabolism 1

Fever HP:0001945

Show evidence (1 reference)

PMID:34292926 SUPPORT Human Clinical

"One or more of the following additional criteria can be used to enhance the specificity of the minimum clinical criteria and support a PID diagnosis:"

Introduces the CDC additional-criteria list whose first entry is oral temperature >38.3 degrees C, establishing fever as a recognized supporting finding. No frequency band is assigned because the guideline states only that the criterion raises specificity, not how often fever is present.

Constitutional 2

Pelvic pain VERY_FREQUENT HP:0034267

Show evidence (1 reference)

PMID:31524362 SUPPORT Human Clinical

"The diagnosis is made primarily on clinical suspicion, and empiric treatment is recommended in sexually active young women or women at risk for sexually transmitted infections who have unexplained lower abdominal or pelvic pain and cervical motion, uterine, or adnexal tenderness on examination."

Lower abdominal or pelvic pain plus pelvic organ tenderness is the clinical trigger for empiric treatment, supporting VERY_FREQUENT for the pain itself.

Chronic pain FREQUENT HP:0012532

Temporal: CHRONIC

Show evidence (1 reference)

PMID:18445635 SUPPORT Human Clinical

"Rates of sequelae, including infertility (22%), recurrent PID (31%) and chronic pelvic pain (42%), were high among women testing positive for endometrial M genitalium at baseline."

42% chronic pelvic pain falls in the FREQUENT band. Note the scope condition: this is the M. genitalium-positive subgroup of a treated trial cohort, not all PID.

Other 8

Endometritis HP:0025636

Show evidence (1 reference)

PMID:34396398 SUPPORT Human Clinical

"Endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis are all on the spectrum of inflammatory processes comprising PID."

Places endometritis within the PID spectrum.

Salpingitis HP:0034492

Show evidence (1 reference)

PMID:25592078 SUPPORT Human Clinical

Establishes salpingitis as the tubal manifestation and its link to functional damage.

Tubo-ovarian abscess HP:0034493

Show evidence (1 reference)

PMID:31524362 SUPPORT Human Clinical

Identifies tubo-ovarian abscess as a recognised complication requiring inpatient care. No frequency band is asserted, because this source establishes the complication without quantifying how often it occurs.

Ectopic pregnancy OCCASIONAL

Deliberately left unbound. HP:0031456 (Ectopic pregnancy) exists but sits under HP:0002686 Pregnancy history, outside the HP:0000118 phenotypic-abnormality root that the PhenotypeTerm enum is reachable from, so it fails term validation. This is another instance of the out-of-root pregnancy-term problem recorded as gap 3 in issue #7837 (alongside HP:0003826 Stillbirth, HP:0009800 Maternal diabetes and HP:0100602 Preeclampsia). No substitute term is bound, because every candidate would be either wrong or so coarse as to lose the claim.

Show evidence (1 reference)

PMID:1411832 SUPPORT Human Clinical

"The ectopic pregnancy rate for first pregnancy after index laparoscopy was 9.1% among the patients and 1.4% among control subjects."

9.1% of first pregnancies after verified PID were ectopic, which falls in the OCCASIONAL band.

Hydrosalpinx HP:6000146

Show evidence (1 reference)

PMID:11779608 SUPPORT Human Clinical

"Five patients with tubal factor infertility who underwent elective salpingectomy because of hydrosalpinges."

Documents hydrosalpinx as the tubal lesion in women with post-inflammatory tubal factor infertility.

Abnormal vaginal discharge HP:0034269

Show evidence (1 reference)

PMID:34292926 SUPPORT Human Clinical

"The majority of women with PID have either mucopurulent cervical discharge or evidence of WBCs on a microscopic evaluation of a saline preparation of vaginal fluid"

Establishes discharge as a majority finding. No frequency band is assigned because the claim is a disjunction with wet-prep leukocytes, so it does not license a majority rate for discharge on its own.

Cervicitis HP:0030160

Show evidence (1 reference)

PMID:34292926 SUPPORT Human Clinical

"the presence of signs of lower genital tract inflammation (predominance of leukocytes in vaginal secretions, cervical discharge, or cervical friability), in addition to one of the three minimum criteria, increases the specificity of the diagnosis."

Names the signs that constitute cervicitis and their diagnostic role in PID.

Abnormal uterine bleeding Abnormal vaginal bleeding HP:0034263

Show evidence (1 reference)

PMID:34292926 SUPPORT Human Clinical

"the patient or the health care provider do not recognize the implications of mild or nonspecific symptoms or signs (e.g., abnormal bleeding, dyspareunia, and vaginal discharge)."

Lists abnormal bleeding among the presenting symptoms of PID. No frequency band is assigned for the same reason as dyspareunia.

💊

Medical Actions

Ceftriaxone

Action: Antibiotic Therapy NCIT:C15620

Agent: ceftriaxone CHEBI:29007

Third-generation cephalosporin given as a single intramuscular dose, the gonococcal-coverage component of the recommended regimen. It is not the component that addresses chlamydial upper tract infection, because beta-lactams do not reach the intracellular compartment where chlamydia replicates.

Mechanism Target:

INHIBITS Ascension to the Upper Genital Tract — Eradicating gonococcal infection of the upper tract removes the organism driving the inflammatory response.

Show evidence (2 references)

PMID:34292926 SUPPORT Human Clinical

"Ceftriaxone has better coverage against N. gonorrhoeae."

Names ceftriaxone specifically as the component of the CDC PID regimen selected for gonococcal coverage, which is the basis for assigning it the INHIBITS edge against gonococcal ascension rather than the doxycycline/metronidazole backbone.

PMID:34292926 SUPPORT Human Clinical

"All regimens used to treat PID should also be effective against N. gonorrhoeae and C. trachomatis because negative endocervical screening for these organisms does not rule out upper genital tract infection."

Establishes that the therapeutic target of the anti-gonococcal component is upper genital tract infection, not merely the endocervical reservoir — the mechanism this edge asserts.

Show evidence (1 reference)

PMID:31524362 SUPPORT Human Clinical

"Mild to moderate disease can be treated in an outpatient setting with a single intramuscular injection of a recommended cephalosporin followed by oral doxycycline for 14 days."

Establishes the single-dose intramuscular cephalosporin as the first component of outpatient therapy.

Doxycycline

Action: Antibiotic Therapy NCIT:C15620

Agent: doxycycline CHEBI:50845

Tetracycline given orally for 14 days, the component of the regimen that reaches intracellular chlamydia. Its role in this entry is not merely additive coverage: it is the drug that satisfies the cell-penetrance requirement created by the intracellular niche, which is why the regimen cannot be simplified to a cephalosporin alone.

Mechanism Target:

INHIBITS Requirement for a Cell-Penetrant Antimicrobial — Doxycycline accumulates intracellularly and is therefore the agent that answers the cell-penetrance constraint this node encodes.

Show evidence (1 reference)

PMID:31524362 SUPPORT Human Clinical

"Mild to moderate disease can be treated in an outpatient setting with a single intramuscular injection of a recommended cephalosporin followed by oral doxycycline for 14 days."

Establishes doxycycline as the recommended partner agent in the regimen.

Show evidence (1 reference)

PMID:34292926 SUPPORT Human Clinical

"Doxycycline 100 mg orally 2 times/day for 14 days with metronidazole 500 mg orally 2 times/day for 14 days"

Gives the recommended dose and duration.

Metronidazole

Action: Antibiotic Therapy NCIT:C15620

Agent: metronidazole CHEBI:6909

Nitroimidazole with anaerobic activity, added to ceftriaxone and doxycycline for 14 days. Its inclusion is the therapeutic expression of the bacterial-vaginosis arm of this entry's pathograph: a randomised placebo-controlled trial showed it reduces endometrial anaerobes, reduces cervical M. genitalium and reduces pelvic tenderness, and it moved from conditional to routine in the 2021 guidelines on that basis.

Mechanism Target:

INHIBITS Loss of Vaginal Lactobacillus Dominance — Metronidazole suppresses the anaerobic consortium that constitutes the bacterial-vaginosis entry route and that is recoverable from the endometrium.

Show evidence (1 reference)

PMID:32052831 SUPPORT Human Clinical

"At 30 days following treatment, anaerobic organisms were less frequently recovered from the endometrium in women treated with metronidazole than placebo (8% vs 21%, P < .05) and cervical Mycoplasma genitalium was reduced (4% vs 14%, P < .05)."

Randomised, placebo-controlled evidence that metronidazole acts on exactly the organisms this node represents, measured in the endometrium.

Show evidence (1 reference)

PMID:32052831 SUPPORT Human Clinical

"In women treated for acute PID, the addition of metronidazole to ceftriaxone and doxycycline was well tolerated and resulted in reduced endometrial anaerobes, decreased M. genitalium, and reduced pelvic tenderness compared to ceftriaxone and doxycycline."

The trial's own conclusion, which is the basis for routine addition of metronidazole.

Outpatient versus inpatient management

Action: Supportive Care NCIT:C15747

Route-of-care decision rather than a distinct drug. The PEACH randomised trial found no difference in reproductive outcomes between inpatient intravenous therapy and outpatient intramuscular-plus-oral therapy for mild-to-moderate disease, which is why outpatient management is the default; hospitalization is reserved for pregnancy, severe illness, outpatient failure, tubo-ovarian abscess, or an unexcluded surgical emergency.

Show evidence (2 references)

PMID:12015517 SUPPORT Human Clinical

"Among women with mild-to-moderate pelvic inflammatory disease, there was no difference in reproductive outcomes between women randomized to inpatient treatment and those randomized to outpatient treatment."

Randomised evidence that the route of care does not change reproductive outcome in mild-to-moderate disease.

PMID:31524362 SUPPORT Human Clinical

Gives the exceptions that override the outpatient default.

Chlamydia screening of at-risk women

Action: Supportive Care NCIT:C15747

Primary prevention rather than treatment of established disease. Identifying and treating cervical chlamydial infection before it ascends is the only intervention in this entry that acts upstream of irreversible tubal damage; a randomised trial roughly halved PID incidence.

Mechanism Target:

INHIBITS Lower Genital Tract Infection and Cervical Colonization — Screening detects and treats the cervical reservoir before ascent occurs, removing the initiating node rather than mitigating its consequences.

Show evidence (1 reference)

PMID:8614421 SUPPORT Human Clinical

"At the end of the follow-up period, there had been 9 verified cases of pelvic inflammatory disease among the women in the screening group and 33 cases among the women receiving usual care (relative risk, 0.44; 95 percent confidence interval, 0.20 to 0.90)."

Randomised evidence that treating the cervical reservoir prevents downstream PID.

Show evidence (1 reference)

PMID:8614421 SUPPORT Human Clinical

"A strategy of identifying, testing, and treating women at increased risk for cervical chlamydial infection was associated with a reduced incidence of pelvic inflammatory disease."

The trial's conclusion supporting screening as PID prevention.

Sex partner treatment

Action: Supportive Care NCIT:C15747

Treatment of sexual partners, including expedited partner therapy where legally permitted. It prevents reinfection, which matters here because the tubal lesion is cumulative in episode number.

Show evidence (1 reference)

PMID:31524362 SUPPORT Human Clinical

"Sex partner treatment is recommended; expedited partner treatment is recommended where legal."

States the recommendation and its legal qualifier.

Drainage or surgery for tubo-ovarian abscess

Action: Drainage NCIT:C50434

Source control when a tubo-ovarian abscess does not respond to parenteral antibiotics. Reserved for medical failure; it addresses the acute-severity branch of the pathograph and does nothing for the fibrotic sequelae.

Mechanism Target:

INHIBITS Tubo-ovarian Abscess and Pelvic Peritonitis — Drainage removes the walled-off collection that antibiotics alone may not sterilize.

Show evidence (1 reference)

PMID:31524362 SUPPORT Human Clinical

Supports tubo-ovarian abscess as an indication for escalation of care. Marked PARTIAL because this source states the hospitalization indication rather than the drainage procedure itself.

🔬

Biochemical Markers

Elevated Erythrocyte Sedimentation Rate (Present)

Context: Supportive laboratory testing in suspected PID

Show evidence (1 reference)

PMID:34292926 SUPPORT Human Clinical

"One or more of the following additional criteria can be used to enhance the specificity of the minimum clinical criteria and support a PID diagnosis:"

Introduces the CDC additional-criteria list, which includes elevated erythrocyte sedimentation rate as a supportive laboratory finding.

Elevated C-Reactive Protein (Present)

Context: Supportive laboratory testing in suspected PID

Show evidence (1 reference)

PMID:34292926 SUPPORT Human Clinical

"One or more of the following additional criteria can be used to enhance the specificity of the minimum clinical criteria and support a PID diagnosis:"

Introduces the CDC additional-criteria list, which includes elevated C-reactive protein as a supportive laboratory finding.

Vaginal Fluid Leukocytes On Saline Microscopy (Present)

Context: Bedside wet-prep microscopy in suspected PID

Show evidence (1 reference)

PMID:34292926 SUPPORT Human Clinical

"If the cervical discharge appears normal and no WBCs are observed on the wet prep of vaginal fluid, a PID diagnosis is unlikely, and alternative causes of pain should be considered."

Establishes the negative predictive value of absent vaginal fluid leukocytes, the basis for curating this as a diagnostic marker rather than a phenotype.

🔬

Diagnosis

Clinical diagnosis with a low empiric-treatment threshold

PID is diagnosed on clinical suspicion. Because the clinical picture is nonspecific and the cost of missing the diagnosis is irreversible tubal damage, guidelines set the treatment threshold deliberately low: pelvic or lower abdominal pain plus cervical motion, uterine or adnexal tenderness in a woman at risk is sufficient. The consequence is that the diagnosed population is not the same as the true-disease population in either direction, which is the main obstacle to interpreting PID epidemiology.

Show evidence (2 references)

PMID:31524362 SUPPORT Human Clinical

States the clinical criteria and the empiric-treatment threshold.

PMID:34396398 SUPPORT Human Clinical

"The clinical diagnosis of PID is nonspecific, creating an urgent need to develop noninvasive tests to diagnose PID."

Establishes the nonspecificity that makes the low threshold necessary and the diagnosed population imprecise.

📊

Prevalence

United States, sexually experienced women aged 18-44 years

Lifetime Prevalence 4400.0 per 100,000 >1 in 1,000

NHANES 2013-2014 self-reported lifetime diagnosis. This is a lifetime prevalence of a clinical diagnosis, not a point prevalence and not a measure of biopsy-confirmed upper tract inflammation; because clinical diagnosis is both insensitive and nonspecific, it is not interchangeable with the true burden of upper genital tract infection.

Show evidence (1 reference)

PMID:34396398 SUPPORT Human Clinical

"approximately 4.4% of all sexually experienced women and 10% of women with a previously diagnosed STI received a diagnosis of PID in their lifetime"

Gives the NHANES lifetime self-reported diagnosis prevalence used for this record.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Pelvic Inflammatory Disease:

Acute appendicitis

Overlapping Features The classic and most dangerous alternative. The reflex of treating any young woman with abdominal pain as PID until proven otherwise has produced ruptured appendices.

Show evidence (1 reference)

PMID:3537321 SUPPORT Other

"This view is dangerous and should be challenged because it has resulted in episodes of ruptured appendix, death from ruptured ectopic pregnancies, and serious morbidity from delayed diagnoses of such entities as diverticulitis and endometriosis."

Names the misdiagnoses that follow from treating PID as the default diagnosis.

Ruptured ectopic pregnancy

Overlapping Features Shares the pain and adnexal tenderness, is immediately life-threatening, and is also a downstream consequence of prior PID — so a history of PID raises rather than lowers the prior for this alternative.

Show evidence (1 reference)

PMID:3537321 SUPPORT Other

Names death from ruptured ectopic pregnancy among the consequences of the PID default.

Endometriosis

Overlapping Features Overlaps on chronic pelvic pain and dyspareunia; distinguished by the cyclical pattern and by laparoscopic appearance.

Show evidence (1 reference)

PMID:3537321 SUPPORT Other

Names endometriosis among the diagnoses delayed by the PID default.

Diverticulitis

Overlapping Features Left-sided pelvic pain with fever, misclassified as PID when the diagnosis is assumed from sex and symptom location.

Show evidence (1 reference)

PMID:3537321 SUPPORT Other

Names diverticulitis among the diagnoses delayed by the PID default.

{ }

Source YAML

click to show

name: Pelvic Inflammatory Disease
creation_date: "2026-08-16T15:40:00Z"
category: Infectious Disease
disease_term:
  preferred_term: pelvic inflammatory disease
  term:
    id: MONDO:0000922
    label: pelvic inflammatory disease
synonyms:
- PID
- acute pelvic inflammatory disease
- salpingitis
- upper genital tract infection
- endometritis-salpingitis-peritonitis syndrome
parents:
- Female reproductive system disorder
- Inflammatory disease
- Bacterial infectious disease
description: >
  Pelvic inflammatory disease is inflammation of the female upper genital tract that
  follows ascent of organisms from the cervix and vagina into the endometrium,
  fallopian tubes, and adjacent pelvic structures. Endometritis, salpingitis,
  tubo-ovarian abscess and pelvic peritonitis are points on one spectrum rather than
  separate diseases. Two features make PID mechanistically distinctive. First, the
  damage that matters clinically is inflicted by the host response, not by the
  organism: gonococcal cell-wall fragments and chlamydial antigens provoke a
  TNF-driven, neutrophil-dominant reaction that sloughs the multiciliated tubal
  epithelium, and the resulting fibrosis and luminal occlusion are irreversible.
  Second, the disease is frequently silent — a large share of tubal factor infertility
  arises in women who never had a symptomatic episode — so the interval between
  infection and diagnosis, rather than the organism's identity, is the strongest
  modifiable determinant of outcome. Neisseria gonorrhoeae and Chlamydia trachomatis
  are the classical pathogens, but fewer than half of contemporary cases yield either;
  Mycoplasma genitalium and the anaerobic consortium of bacterial vaginosis account for
  a substantial further fraction, and this etiological shift is not fully covered by
  the recommended regimen.
references:
- reference: PMID:34396413
  title: "Pelvic Inflammatory Disease Due to Neisseria gonorrhoeae and Chlamydia trachomatis: Immune Evasion Mechanisms and Pathogenic Disease Pathways."
  findings:
  - statement: >
      PID follows ascension of sexually transmitted pathogens from the lower genital
      tract, and both classical pathogens survive intracellularly and actively evade
      innate and adaptive immunity.
  - statement: >
      Endometrial transcriptional profiling in women with PID shows myeloid, cell death
      and innate inflammatory pathway activation alongside suppressed T-cell activation.
- reference: PMID:34396398
  title: "A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease."
  findings:
  - statement: >
      Fewer than half of women diagnosed with PID have gonococcal or chlamydial
      infection; M. genitalium, respiratory pathogens and bacterial-vaginosis-associated
      bacteria account for a substantial fraction.
  - statement: >
      The clinical diagnosis is nonspecific and there is no validated noninvasive test.
- reference: PMID:25592078
  title: "Pathogenesis of fallopian tube damage caused by Chlamydia trachomatis infections."
  findings:
  - statement: >
      Permanent tubal damage in chlamydial infection is a consequence of the host innate
      and adaptive immune response to ongoing or repeated infection rather than of direct
      microbial cytotoxicity.
- reference: PMID:1411832
  title: "Pelvic inflammatory disease and fertility. A cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results."
  findings:
  - statement: >
      The reference cohort quantifying tubal factor infertility and ectopic pregnancy
      after laparoscopically confirmed PID, and the dose-response with episode number
      and severity.
- reference: PMID:31524362
  title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
  findings:
  - statement: >
      Contemporary clinical review covering the empiric-treatment threshold, the
      outpatient cephalosporin-plus-doxycycline regimen, indications for hospitalization,
      and partner treatment.

prevalence:
- population: United States, sexually experienced women aged 18-44 years
  measure_type: LIFETIME_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 4400.0
  notes: >
    NHANES 2013-2014 self-reported lifetime diagnosis. This is a lifetime prevalence of
    a clinical diagnosis, not a point prevalence and not a measure of biopsy-confirmed
    upper tract inflammation; because clinical diagnosis is both insensitive and
    nonspecific, it is not interchangeable with the true burden of upper genital tract
    infection.
  evidence:
  - reference: PMID:34396398
    reference_title: "A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "approximately 4.4% of all sexually experienced women and 10% of women with a previously diagnosed STI received a diagnosis of PID in their lifetime"
    explanation: >
      Gives the NHANES lifetime self-reported diagnosis prevalence used for this record.

pathophysiology:
- name: Lower Genital Tract Infection and Cervical Colonization
  biological_scale: TISSUE
  description: >
    Establishment of Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium
    or bacterial-vaginosis-associated anaerobes at the endocervix. This is the reservoir
    from which the upper tract is seeded, and it is where the disease is interruptible:
    detecting and treating cervical infection at this stage prevents PID, whereas nothing
    downstream reverses tubal damage once it has occurred. Most cervical infection is
    asymptomatic, which is why the node is usually crossed unobserved.
  biological_processes:
  - preferred_term: biological process involved in interaction with host
    term:
      id: GO:0051701
      label: biological process involved in interaction with host
  locations:
  - preferred_term: uterine cervix
    term:
      id: UBERON:0000002
      label: uterine cervix
  evidence:
  - reference: PMID:34396413
    reference_title: "Pelvic Inflammatory Disease Due to Neisseria gonorrhoeae and Chlamydia trachomatis: Immune Evasion Mechanisms and Pathogenic Disease Pathways."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neisseria gonorrhoeae and Chlamydia trachomatis are the 2 most commonly recognized PID pathogens."
    explanation: >
      Names the two classical organisms colonizing the lower tract before ascent.
  - reference: PMID:34396398
    reference_title: "A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent studies of women with PID have reported that fewer than half of women receiving a diagnosis of PID have gonococcal or chlamydial infection, while Mycoplasma genitalium, respiratory pathogens, and the constellation of bacteria associated with bacterial vaginosis may account for a substantial fraction of PID cases."
    explanation: >
      Establishes that the causative organism pool is broader than the two classical
      pathogens, which is why this node is not named for a single species.
  downstream:
  - target: Ascension to the Upper Genital Tract
    causal_link_type: DIRECT
    description: >
      Organisms established at the cervix move upward into the endometrial cavity and
      fallopian tubes.
    evidence:
    - reference: PMID:34396413
      reference_title: "Pelvic Inflammatory Disease Due to Neisseria gonorrhoeae and Chlamydia trachomatis: Immune Evasion Mechanisms and Pathogenic Disease Pathways."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pelvic inflammatory disease (PID) results from ascension of sexually transmitted pathogens from the lower genital tract to the uterus and/or fallopian tubes in women, with potential spread to neighboring pelvic organs."
      explanation: >
        States the ascent from lower to upper genital tract as the defining causal step.

- name: Loss of Vaginal Lactobacillus Dominance
  biological_scale: TISSUE
  description: >
    Replacement of a lactobacillus-dominated vaginal community by a diverse anaerobic
    consortium (Gardnerella vaginalis, Megasphaera, Atopobium). This is the bacterial
    vaginosis arm of PID: it supplies organisms that can themselves ascend, and it is the
    reason anaerobic coverage is part of the regimen. It is curated as a parallel entry
    route rather than as a step in the sexually transmitted chain, because it does not
    require acquisition of a classical STI pathogen.
  biological_processes:
  - preferred_term: biological process involved in interaction with host
    term:
      id: GO:0051701
      label: biological process involved in interaction with host
    modifier: ABNORMAL
  locations:
  - preferred_term: vagina
    term:
      id: UBERON:0000996
      label: vagina
  evidence:
  - reference: PMID:33091407
    reference_title: "Bacterial vaginosis and its association with infertility, endometritis, and pelvic inflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bacterial vaginosis is characterized by a lower prevalence of lactobacilli and a higher prevalence of anaerobic bacteria, including Gardnerella vaginalis, Megasphaera spp., and Atopobium vaginae."
    explanation: >
      Defines the microbial shift this node represents.
  - reference: PMID:32052831
    reference_title: "A Randomized Controlled Trial of Ceftriaxone and Doxycycline, With or Without Metronidazole, for the Treatment of Acute Pelvic Inflammatory Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anaerobic organisms are important pathogens in acute pelvic inflammatory disease (PID)."
    explanation: >
      Independent trial-based statement that anaerobes are genuine PID pathogens, not
      bystanders, supporting this as a causal node.
  downstream:
  - target: Ascension to the Upper Genital Tract
    causal_link_type: UNKNOWN
    description: >
      Anaerobes from the disturbed vaginal community reach the endometrium. The edge is
      typed UNKNOWN deliberately: the association with endometritis and PID is well
      documented, but the review that states it also states that the mechanism of ascent
      is unclear.
    evidence:
    - reference: PMID:33091407
      reference_title: "Bacterial vaginosis and its association with infertility, endometritis, and pelvic inflammatory disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Endometritis and pelvic inflammatory disease are caused by the ascension of pathogenic bacteria to the uterus, although the mechanisms by which they do so are unclear."
      explanation: >
        Supports the ascent while explicitly disclaiming knowledge of the mechanism, which
        is why the edge is typed UNKNOWN and the evidence marked PARTIAL.

- name: Ascension to the Upper Genital Tract
  biological_scale: TISSUE
  description: >
    Arrival of organisms in the endometrial cavity and fallopian tubes, producing the
    endometritis-salpingitis spectrum that is PID. Because the endometrium and tube are
    contiguous, the same event is named endometritis, salpingitis, tubo-ovarian abscess
    or pelvic peritonitis depending on how far it has extended, and these are not
    separate diseases.
  cell_types:
  - preferred_term: fallopian tube multiciliated epithelial cell
    term:
      id: CL:4030007
      label: fallopian tube multiciliated epithelial cell
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  - preferred_term: fallopian tube
    term:
      id: UBERON:0003889
      label: fallopian tube
  evidence:
  - reference: PMID:34396398
    reference_title: "A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis are all on the spectrum of inflammatory processes comprising PID."
    explanation: >
      States that the named clinical entities are one spectrum, which is what this node
      represents.
  - reference: PMID:25592078
    reference_title: "Pathogenesis of fallopian tube damage caused by Chlamydia trachomatis infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If infections are either not resolved or left untreated, chlamydia can ascend to the upper FGT and infect the fallopian tubes (FTs) causing salpingitis that may lead to functional damage of the FTs and tubal factor infertility (TFI)."
    explanation: >
      Traces the chain from untreated lower tract infection through ascent to salpingitis
      and functional tubal damage.
  downstream:
  - target: Intracellular Survival and Innate Immune Evasion
    causal_link_type: DIRECT
    description: >
      Organisms that reach the upper tract invade and persist within tubal epithelium and
      recruited phagocytes.
  - target: Neutrophil-Dominant Innate Inflammation with Dampened T-Cell Activation
    causal_link_type: DIRECT
    description: >
      Upper tract infection provokes an innate, myeloid-dominated inflammatory response in
      the endometrium.
    evidence:
    - reference: PMID:34396413
      reference_title: "Pelvic Inflammatory Disease Due to Neisseria gonorrhoeae and Chlamydia trachomatis: Immune Evasion Mechanisms and Pathogenic Disease Pathways."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A study of women with N. gonorrhoeae- and/or C. trachomatis-induced PID with histologic endometritis revealed activation of myeloid cell, cell death, and innate inflammatory pathways in conjunction with dampening of T-cell activation pathways."
      explanation: >
        Human endometrial-disease transcriptional evidence for the character of the
        response this edge produces.
  - target: Tubo-ovarian Abscess and Pelvic Peritonitis
    causal_link_type: DIRECT
    description: >
      Continued spread beyond the tubal lumen to the ovary and peritoneal cavity.
    evidence:
    - reference: PMID:34396398
      reference_title: "A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis are all on the spectrum of inflammatory processes comprising PID."
      explanation: >
        Places abscess and peritonitis at the extended end of the same spectrum.

- name: Intracellular Survival and Innate Immune Evasion
  biological_scale: CELLULAR
  description: >
    Both classical PID pathogens persist inside host epithelial cells and neutrophils and
    actively subvert the innate response, which is why the infection is chronic and why
    the therapeutic requirement is for an agent that reaches the intracellular
    compartment. This is the lifestyle-gating step: it constrains which drugs can work,
    independently of any organism's in vitro susceptibility.
  conforms_to: "intracellular_pathogen_persistence#Intracellular Niche and Beta-Lactam Exclusion"
  role: intrinsic_resistance
  cell_types:
  - preferred_term: fallopian tube multiciliated epithelial cell
    term:
      id: CL:4030007
      label: fallopian tube multiciliated epithelial cell
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: biological process involved in interaction with host
    term:
      id: GO:0051701
      label: biological process involved in interaction with host
  evidence:
  - reference: PMID:34396413
    reference_title: "Pelvic Inflammatory Disease Due to Neisseria gonorrhoeae and Chlamydia trachomatis: Immune Evasion Mechanisms and Pathogenic Disease Pathways."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their ability to survive within host epithelial cells and neutrophils highlights a need for T-cell-mediated production of interferon γ in protection."
    explanation: >
      States the intracellular niche in the two classical PID pathogens, which is the
      module's gating condition.
  - reference: PMID:34396413
    reference_title: "Pelvic Inflammatory Disease Due to Neisseria gonorrhoeae and Chlamydia trachomatis: Immune Evasion Mechanisms and Pathogenic Disease Pathways."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both pathogens exert multiple mechanisms of immune evasion that benefit themselves and each other at the expense of the host."
    explanation: >
      Supports the active immune-evasion component of this node, curated separately from
      the intracellular-niche claim because it is a distinct assertion.
  - reference: PMID:18611821
    reference_title: "Intracellular organisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The intracellular location of some microorganisms allow them to resist antibiotics with poor ability to penetrate eukaryotic cell membranes, such as the beta-lactam compounds."
    explanation: >
      The general principle the module encodes, cited here to justify the conformance
      rather than to assert anything PID-specific. Evidence source OTHER as this is a
      review.
  downstream:
  - target: Requirement for a Cell-Penetrant Antimicrobial
    causal_link_type: DIRECT
    description: >
      Because the organisms sit inside host cells, effective therapy is restricted to
      agents that accumulate intracellularly.

- name: Requirement for a Cell-Penetrant Antimicrobial
  biological_scale: MOLECULAR
  description: >
    The therapeutic consequence of the intracellular niche: efficacy tracks the
    intracellular concentration achieved rather than the in vitro MIC, so doxycycline
    rather than the cephalosporin is the component of the PID regimen that addresses
    chlamydial upper tract infection. This node exists to carry that constraint
    explicitly; it is why every recommended PID regimen pairs a cephalosporin with a
    tetracycline instead of escalating the cephalosporin.
  conforms_to: "intracellular_pathogen_persistence#Requirement for Cell-Penetrant Antimicrobials"
  role: therapeutic_vulnerability
  biological_processes:
  - preferred_term: response to antibiotic
    term:
      id: GO:0046677
      label: response to antibiotic
  evidence:
  - reference: PMID:28639230
    reference_title: "Intracellular Pharmacokinetics of Antibacterials and Their Clinical Implications."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Therapeutic efficacy against intracellular pathogens has been correlated mainly with the intracellular concentrations achieved by the different antimicrobial agents."
    explanation: >
      The pharmacokinetic principle the node encodes. Evidence source OTHER as this is a
      review.
  - reference: PMID:31524362
    reference_title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild to moderate disease can be treated in an outpatient setting with a single intramuscular injection of a recommended cephalosporin followed by oral doxycycline for 14 days."
    explanation: >
      Shows the recommended regimen pairing a cephalosporin with the cell-penetrant
      tetracycline, which is the clinical expression of this requirement.

- name: Neutrophil-Dominant Innate Inflammation with Dampened T-Cell Activation
  biological_scale: TISSUE
  description: >
    The host response that actually causes the damage. Endometrial tissue from women with
    histologically confirmed PID shows activation of myeloid, cell death and innate
    inflammatory programmes together with suppression of T-cell activation — an
    inflammatory response that is intense but non-protective, which is consistent with the
    absence of durable immunity after natural infection and with the high rate of
    reinfection.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
    modifier: DECREASED
  biological_processes:
  - preferred_term: neutrophil chemotaxis
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
    modifier: INCREASED
  - preferred_term: tumor necrosis factor production
    term:
      id: GO:0032640
      label: tumor necrosis factor production
    modifier: INCREASED
  locations:
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  evidence:
  - reference: PMID:34396413
    reference_title: "Pelvic Inflammatory Disease Due to Neisseria gonorrhoeae and Chlamydia trachomatis: Immune Evasion Mechanisms and Pathogenic Disease Pathways."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A study of women with N. gonorrhoeae- and/or C. trachomatis-induced PID with histologic endometritis revealed activation of myeloid cell, cell death, and innate inflammatory pathways in conjunction with dampening of T-cell activation pathways."
    explanation: >
      Direct human tissue-level evidence for both halves of this node: innate activation
      and suppressed T-cell activation.
  - reference: PMID:25592078
    reference_title: "Pathogenesis of fallopian tube damage caused by Chlamydia trachomatis infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chlamydial pathogenesis of irreversible and permanent tubal damage is a consequence of innate and adaptive host immune responses to ongoing or repeated infections."
    explanation: >
      States explicitly that the permanent damage is caused by the host response, which is
      the organising claim of this node.
  downstream:
  - target: TNF-Mediated Sloughing of Ciliated Tubal Epithelium
    causal_link_type: DIRECT
    description: >
      Mucosal TNF-alpha produced during infection is the proximate mediator of ciliated
      cell loss.
    evidence:
    - reference: PMID:10100774
      reference_title: "Gonococcal infection of human fallopian tube mucosa in organ culture: relationship of mucosal tissue TNF-alpha concentration to sloughing of ciliated cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "There was a close and statistically significant correlation between the TNF-alpha mucosal tissue concentration and the proportion of ciliated cells lost from the mucosa as measured by the PPCA (r = 0.95, p < 0.001)."
      explanation: >
        Quantitative dose-response between mucosal TNF-alpha and ciliated cell loss in
        human fallopian tube organ culture.
  - target: Chlamydial HSP60-Directed Immunopathology
    causal_link_type: DIRECT
    description: >
      In chlamydial disease the adaptive arm of the same response is directed at cHSP60
      released from infected cells.

- name: TNF-Mediated Sloughing of Ciliated Tubal Epithelium
  biological_scale: CELLULAR
  description: >
    Detachment and loss of the multiciliated cells lining the tubal mucosa, the lesion
    that converts a transient infection into permanent transport failure. The classical
    human fallopian tube organ culture work established that this is not direct bacterial
    cytotoxicity: purified gonococcal peptidoglycan monomers reproduce the damage in the
    absence of live organisms, and recombinant TNF-alpha alone is sufficient. Because the
    ciliated epithelium does not regenerate its function, this node is the point at which
    the disease becomes irreversible.
  cell_types:
  - preferred_term: fallopian tube multiciliated epithelial cell
    term:
      id: CL:4030007
      label: fallopian tube multiciliated epithelial cell
    modifier: DECREASED
  biological_processes:
  - preferred_term: cilium movement
    term:
      id: GO:0003341
      label: cilium movement
    modifier: DECREASED
  locations:
  - preferred_term: fallopian tube
    term:
      id: UBERON:0003889
      label: fallopian tube
  evidence:
  - reference: PMID:10100774
    reference_title: "Gonococcal infection of human fallopian tube mucosa in organ culture: relationship of mucosal tissue TNF-alpha concentration to sloughing of ciliated cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Gonococcal infection of human fallopian tube mucosa in organ culture results in the sloughing of ciliated epithelial cells from the mucosa."
    explanation: >
      Establishes the lesion itself in the human ex vivo model.
  - reference: PMID:6425421
    reference_title: "Ability of monomeric peptidoglycan fragments from Neisseria gonorrhoeae to damage human fallopian-tube mucosa."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The damage produced by either of these peptidoglycan monomers resulted in sloughing of ciliated cells from the mucosa and resembled the damage observed in active gonococcal infection"
    explanation: >
      Shows that a purified bacterial cell-wall fragment reproduces the lesion without
      live organisms, which is the evidence that the damage is host-mediated rather than
      an effect of bacterial invasion.
  downstream:
  - target: Tubal Fibrosis and Luminal Occlusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Repeated or sustained epithelial destruction is followed by scarring of the tube.
      The edge is typed INDIRECT_UNKNOWN_INTERMEDIATES because the human evidence links
      the inflammatory response to fibrosis and occlusion as an outcome, without
      identifying the mesenchymal steps in between.
    evidence:
    - reference: PMID:25592078
      reference_title: "Pathogenesis of fallopian tube damage caused by Chlamydia trachomatis infections."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chlamydial pathogenesis of irreversible and permanent tubal damage is a consequence of innate and adaptive host immune responses to ongoing or repeated infections."
      explanation: >
        Supports inflammation-driven permanent tubal damage after repeated infection while
        leaving the intervening fibrogenic steps unspecified.
  - target: Tubal Factor Infertility
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Loss of ciliary transport, together with subsequent scarring, prevents normal
      gamete and embryo transport.
    evidence:
    - reference: PMID:10100774
      reference_title: "Gonococcal infection of human fallopian tube mucosa in organ culture: relationship of mucosal tissue TNF-alpha concentration to sloughing of ciliated cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "supports the hypothesis that induction of the proinflammatory cytokine, TNF-alpha, by gonococcal infection, with resultant inflammation and sloughing of ciliated cells, is an important pathogenic mechanism of gonococcal salpingitis and may mediate postsalpingitis infertility and ectopic pregnancy as well."
      explanation: >
        The authors' own hypothesis statement linking ciliated cell loss to postsalpingitis
        infertility and ectopic pregnancy. Marked PARTIAL because the paper states this as
        a supported hypothesis, not a demonstrated clinical result.

- name: Chlamydial HSP60-Directed Immunopathology
  biological_scale: CELLULAR
  description: >
    The chlamydia-specific arm of the immunopathology. Chlamydial heat shock protein 60,
    released when infected cells lyse, is recognised by T-cell clones recoverable from
    inflamed salpingeal tissue of women with tubal factor infertility, and drives the
    proinflammatory response that ends in fibrosis. Curated as a separate node from the
    generic innate response because the antigen, the effector cell type and the clinical
    correlate are all specific to chlamydia.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
    modifier: INCREASED
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: fallopian tube
    term:
      id: UBERON:0003889
      label: fallopian tube
  evidence:
  - reference: PMID:11779608
    reference_title: "Chlamydial heat shock protein 60--specific T cells in inflamed salpingeal tissue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Seventy-seven (34%) of the 229 T-lymphocyte clones recognized C. trachomatis and C. pneumoniae elementary bodies as target antigens. One-third of these Chlamydia genus-specific T-lymphocyte clones further recognized CHSP60 as the target antigen."
    explanation: >
      Recovery and cloning of cHSP60-reactive T cells from salpingeal tissue of women with
      tubal factor infertility. Classified IN_VITRO because the measurement is on cultured
      T-lymphocyte clones, although the tissue was human surgical material.
  - reference: PMID:25592078
    reference_title: "Pathogenesis of fallopian tube damage caused by Chlamydia trachomatis infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When released from infected cells, cHSP60 can induce proinflammatory immune responses that may functionally impair the FTs leading to fibrosis and luminal occlusion."
    explanation: >
      States the cHSP60 release, proinflammatory response and fibrotic endpoint that this
      node encodes.
  downstream:
  - target: Tubal Fibrosis and Luminal Occlusion
    causal_link_type: DIRECT
    description: >
      cHSP60-driven inflammation is the proposed route to fibrosis and occlusion of the
      tubal lumen in chlamydial disease.
    evidence:
    - reference: PMID:11779608
      reference_title: "Chlamydial heat shock protein 60--specific T cells in inflamed salpingeal tissue."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "CHSP60 may be an important T-lymphocyte antigen involved in the immunopathogenesis of tubal damage associated with chronic C. trachomatis infection."
      explanation: >
        The authors' hedged conclusion is preserved as PARTIAL rather than upgraded, since
        the study is a five-patient case series.

- name: Tubal Fibrosis and Luminal Occlusion
  biological_scale: TISSUE
  description: >
    Replacement of damaged tubal mucosa by scar, with adhesion formation and narrowing or
    closure of the lumen; hydrosalpinx is its imaged form. Matrix metalloproteinase
    regulation of the extracellular matrix is implicated. This is the structural lesion
    that all the downstream reproductive consequences share.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DYSREGULATED
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: INCREASED
  locations:
  - preferred_term: fallopian tube
    term:
      id: UBERON:0003889
      label: fallopian tube
  evidence:
  - reference: PMID:25592078
    reference_title: "Pathogenesis of fallopian tube damage caused by Chlamydia trachomatis infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When released from infected cells, cHSP60 can induce proinflammatory immune responses that may functionally impair the FTs leading to fibrosis and luminal occlusion."
    explanation: >
      Names fibrosis and luminal occlusion as the endpoint of the tubal inflammatory
      response.
  - reference: PMID:25592078
    reference_title: "Pathogenesis of fallopian tube damage caused by Chlamydia trachomatis infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The extracellular matrix that is regulated by metalloproteinases may also be modified by chlamydial infections of the FGT."
    explanation: >
      Supports the matrix-remodelling annotation on this node. Marked PARTIAL because the
      review states it as a possibility rather than an established finding, which is also
      why no fibrotic_response module conformance is claimed here.
  downstream:
  - target: Tubal Factor Infertility
    causal_link_type: DIRECT
    description: >
      An occluded or scarred tube cannot transport gametes or the embryo.
    evidence:
    - reference: PMID:1411832
      reference_title: "Pelvic inflammatory disease and fertility. A cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A total of 141 (10.8%) of the patients and 0 (0%) of the control subjects had confirmed tubal factor infertility"
      explanation: >
        Cohort evidence that confirmed tubal factor infertility occurs after
        laparoscopically verified PID and in none of the laparoscopy-normal controls.
  - target: Ectopic Implantation
    causal_link_type: DIRECT
    description: >
      A partially patent, scarred tube retains the embryo rather than transporting it,
      permitting tubal implantation.
    evidence:
    - reference: PMID:34396398
      reference_title: "A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Scarring of the fallopian tube can also lead to ectopic pregnancy which is a cause of death in women of reproductive age globally."
      explanation: >
        States the causal link from tubal scarring to ectopic pregnancy and its mortality
        significance.
  - target: Chronic Pelvic Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Post-inflammatory adhesive disease is the usual explanation offered for persistent
      pain after PID, but the mechanism connecting the structural lesion to the pain
      syndrome is not established; the edge is typed accordingly.

- name: Tubo-ovarian Abscess and Pelvic Peritonitis
  biological_scale: TISSUE
  description: >
    Extension of infection beyond the tubal lumen into a walled-off adnexal collection
    and onto the peritoneal surface. This is the acute-severity branch: it is the branch
    that requires hospitalization and, when medical therapy fails, drainage or surgery,
    and it is what makes PID an occasionally surgical disease rather than a purely
    outpatient one.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: neutrophil chemotaxis
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
    modifier: INCREASED
  locations:
  - preferred_term: ovary
    term:
      id: UBERON:0000992
      label: ovary
  - preferred_term: peritoneum
    term:
      id: UBERON:0002358
      label: peritoneum
  evidence:
  - reference: PMID:31524362
    reference_title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hospitalization for parenteral antibiotics is recommended in patients who are pregnant or severely ill, in whom outpatient treatment has failed, those with tubo-ovarian abscess, or if surgical emergencies cannot be excluded."
    explanation: >
      Establishes tubo-ovarian abscess as the branch that changes management, which is why
      it is modelled as its own node.

- name: Subclinical Upper Genital Tract Inflammation
  biological_scale: TISSUE
  description: >
    Histologic endometritis without a symptomatic PID episode. This is the most
    consequential feature of the disease for the knowledge base, because it breaks the
    assumption that treating the diagnosable disease prevents the sequelae: in a
    prospective cohort, women with biopsy-defined subclinical PID had a 40% lower
    incidence of pregnancy despite receiving treatment for their gonococcal, chlamydial
    or bacterial-vaginosis infection, while women with those infections but without
    subclinical PID were not at increased risk. Most tubal factor infertility therefore
    arises along a route that current care does not intercept.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  evidence:
  - reference: PMID:22678036
    reference_title: "Subclinical pelvic inflammatory disease and infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Women with subclinical PID diagnosed at enrollment had a 40% reduced incidence of pregnancy compared with women without subclinical PID (hazard ratio 0.6, 95% confidence interval 0.4-0.8)."
    explanation: >
      Prospective cohort quantifying the fertility cost of subclinical endometritis.
  - reference: PMID:34396413
    reference_title: "Pelvic Inflammatory Disease Due to Neisseria gonorrhoeae and Chlamydia trachomatis: Immune Evasion Mechanisms and Pathogenic Disease Pathways."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since most women with tubal factor infertility have no history of symptomatic PID, damage to the fallopian tubes may occur with subclinical infections"
    explanation: >
      Independent statement that the majority of tubal factor infertility follows
      subclinical rather than symptomatic disease.
  downstream:
  - target: Tubal Factor Infertility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Subclinical endometritis reduces subsequent fertility even when the associated lower
      tract infection is treated. The intervening tubal events are not observed in these
      women, since the cohort endpoint is fertility rather than tubal morphology.
    evidence:
    - reference: PMID:22678036
      reference_title: "Subclinical pelvic inflammatory disease and infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Subclinical PID decreases subsequent fertility despite provision of treatment for sexually transmitted diseases."
      explanation: >
        The authors' conclusion, which is both the causal claim and the statement that
        treatment does not abolish it.

- name: Tubal Factor Infertility
  biological_scale: ORGANISM
  description: >
    Inability to conceive attributable to tubal damage. Risk rises with the number and
    severity of PID episodes, which is the clearest available evidence that the lesion is
    cumulative rather than all-or-none.
  locations:
  - preferred_term: fallopian tube
    term:
      id: UBERON:0003889
      label: fallopian tube
  evidence:
  - reference: PMID:1411832
    reference_title: "Pelvic inflammatory disease and fertility. A cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tubal factor infertility after PID was associated with number and severity of PID episodes."
    explanation: >
      Establishes the dose-response with episode count and severity.

- name: Ectopic Implantation
  biological_scale: ORGANISM
  description: >
    Implantation of the conceptus in the damaged tube. The Westrom cohort puts the
    ectopic rate for the first pregnancy after laparoscopically verified PID at 9.1%
    against 1.4% in laparoscopy-normal controls, an approximately sixfold excess. This
    node is the point of contact between this entry and the separate Ectopic Pregnancy
    entry, which models the implantation event itself.
  locations:
  - preferred_term: fallopian tube
    term:
      id: UBERON:0003889
      label: fallopian tube
  evidence:
  - reference: PMID:1411832
    reference_title: "Pelvic inflammatory disease and fertility. A cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ectopic pregnancy rate for first pregnancy after index laparoscopy was 9.1% among the patients and 1.4% among control subjects."
    explanation: >
      Quantifies the ectopic pregnancy excess after verified PID against a
      laparoscopically normal comparison group.

- name: Chronic Pelvic Pain
  biological_scale: ORGANISM
  description: >
    Persistent pelvic pain after the acute episode, the most common long-term complaint
    and the one least well explained mechanistically. It is frequent enough after PID to
    be a defining sequela — 42% among women with endometrial M. genitalium in the PEACH
    substudy — yet no node in this pathograph accounts for it in mechanistic terms, which
    is recorded as a knowledge gap rather than papered over.
  evidence:
  - reference: PMID:31524362
    reference_title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Untreated PID can lead to chronic pelvic pain, infertility, ectopic pregnancy, and intra-abdominal infections."
    explanation: >
      Names chronic pelvic pain among the established sequelae of untreated PID.
  - reference: PMID:18445635
    reference_title: "Failure of cefoxitin and doxycycline to eradicate endometrial Mycoplasma genitalium and the consequence for clinical cure of pelvic inflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rates of sequelae, including infertility (22%), recurrent PID (31%) and chronic pelvic pain (42%), were high among women testing positive for endometrial M genitalium at baseline."
    explanation: >
      Quantifies the sequela rates in a treated PID trial population.

- name: Delayed Presentation and Treatment
  biological_scale: ORGANISM
  description: >
    The interval between symptom onset and effective therapy, curated as a node rather
    than as context because it is the strongest modifiable determinant of outcome in this
    disease and because it acts on the pathograph — it lengthens the period during which
    the inflammatory lesion accumulates. Delay is driven by the nonspecific clinical
    picture and by the absence of any validated noninvasive diagnostic test.
  evidence:
  - reference: PMID:8498436
    reference_title: "Delayed care of pelvic inflammatory disease as a risk factor for impaired fertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Women who delayed seeking care for pelvic inflammatory disease were three times more likely to experience infertility or ectopic pregnancy than women who sought care promptly"
    explanation: >
      Quantifies the effect of delay on the two principal reproductive sequelae.
  - reference: PMID:34396398
    reference_title: "A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical diagnosis of PID is nonspecific, creating an urgent need to develop noninvasive tests to diagnose PID."
    explanation: >
      Identifies the diagnostic imprecision that produces the delay.
  downstream:
  - target: Tubal Fibrosis and Luminal Occlusion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Delay prolongs the inflammatory phase, allowing more tubal damage to accumulate
      before it is arrested.
    evidence:
    - reference: PMID:8498436
      reference_title: "Delayed care of pelvic inflammatory disease as a risk factor for impaired fertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "our data suggest that prompt evaluation and treatment of chlamydial pelvic inflammatory disease can prevent these sequelae"
      explanation: >
        The converse formulation — prompt treatment prevents the sequelae — supports delay
        acting through accumulating tubal damage. Marked PARTIAL because the study measures
        the reproductive endpoints, not tubal morphology.

phenotypes:
- name: Pelvic pain
  category: Clinical
  description: >
    Lower abdominal or pelvic pain, usually bilateral, the presenting complaint in
    symptomatic disease and the basis of the empiric-treatment threshold.
  phenotype_term:
    preferred_term: Pelvic pain
    term:
      id: HP:0034267
      label: Pelvic pain
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31524362
    reference_title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis is made primarily on clinical suspicion, and empiric treatment is recommended in sexually active young women or women at risk for sexually transmitted infections who have unexplained lower abdominal or pelvic pain and cervical motion, uterine, or adnexal tenderness on examination."
    explanation: >
      Lower abdominal or pelvic pain plus pelvic organ tenderness is the clinical trigger
      for empiric treatment, supporting VERY_FREQUENT for the pain itself.
- name: Endometritis
  category: Clinical
  description: >
    Inflammation of the endometrium, demonstrable histologically on endometrial biopsy and
    present in both symptomatic and subclinical disease.
  phenotype_term:
    preferred_term: Endometritis
    term:
      id: HP:0025636
      label: Endometritis
  evidence:
  - reference: PMID:34396398
    reference_title: "A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis are all on the spectrum of inflammatory processes comprising PID."
    explanation: >
      Places endometritis within the PID spectrum.
- name: Salpingitis
  category: Clinical
  description: >
    Inflammation of the fallopian tube, the lesion responsible for the reproductive
    sequelae and the finding sought at diagnostic laparoscopy.
  phenotype_term:
    preferred_term: Salpingitis
    term:
      id: HP:0034492
      label: Salpingitis
  evidence:
  - reference: PMID:25592078
    reference_title: "Pathogenesis of fallopian tube damage caused by Chlamydia trachomatis infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If infections are either not resolved or left untreated, chlamydia can ascend to the upper FGT and infect the fallopian tubes (FTs) causing salpingitis that may lead to functional damage of the FTs and tubal factor infertility (TFI)."
    explanation: >
      Establishes salpingitis as the tubal manifestation and its link to functional damage.
- name: Tubo-ovarian abscess
  category: Clinical
  description: >
    Walled-off adnexal collection involving tube and ovary; an indication for
    hospitalization and, on medical failure, drainage or surgery.
  phenotype_term:
    preferred_term: Tubo-ovarian abscess
    term:
      id: HP:0034493
      label: Tubo-ovarian abscess
  evidence:
  - reference: PMID:31524362
    reference_title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hospitalization for parenteral antibiotics is recommended in patients who are pregnant or severely ill, in whom outpatient treatment has failed, those with tubo-ovarian abscess, or if surgical emergencies cannot be excluded."
    explanation: >
      Identifies tubo-ovarian abscess as a recognised complication requiring inpatient
      care. No frequency band is asserted, because this source establishes the complication
      without quantifying how often it occurs.
- name: Peritonitis
  category: Clinical
  description: >
    Pelvic peritoneal inflammation at the extended end of the PID spectrum.
  phenotype_term:
    preferred_term: Peritonitis
    term:
      id: HP:0002586
      label: Peritonitis
  evidence:
  - reference: PMID:34396398
    reference_title: "A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis are all on the spectrum of inflammatory processes comprising PID."
    explanation: >
      Places pelvic peritonitis within the PID spectrum.
- name: Female infertility
  category: Clinical
  description: >
    Tubal factor infertility following tubal scarring and occlusion; the dominant
    long-term morbidity.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:1411832
    reference_title: "Pelvic inflammatory disease and fertility. A cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 141 (10.8%) of the patients and 0 (0%) of the control subjects had confirmed tubal factor infertility"
    explanation: >
      10.8% confirmed tubal factor infertility among women with laparoscopically verified
      PID, which falls in the OCCASIONAL band (5-29%).
- name: Ectopic pregnancy
  category: Clinical
  description: >
    Tubal implantation in a subsequent pregnancy, roughly sixfold more common after
    verified PID than in laparoscopy-normal controls.
  phenotype_term:
    preferred_term: Ectopic pregnancy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:1411832
    reference_title: "Pelvic inflammatory disease and fertility. A cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ectopic pregnancy rate for first pregnancy after index laparoscopy was 9.1% among the patients and 1.4% among control subjects."
    explanation: >
      9.1% of first pregnancies after verified PID were ectopic, which falls in the
      OCCASIONAL band.
  notes: >
    Deliberately left unbound. HP:0031456 (Ectopic pregnancy) exists but sits under
    HP:0002686 Pregnancy history, outside the HP:0000118 phenotypic-abnormality root that
    the PhenotypeTerm enum is reachable from, so it fails term validation. This is another
    instance of the out-of-root pregnancy-term problem recorded as gap 3 in issue #7837
    (alongside HP:0003826 Stillbirth, HP:0009800 Maternal diabetes and HP:0100602
    Preeclampsia). No substitute term is bound, because every candidate would be either
    wrong or so coarse as to lose the claim.
- name: Chronic pain
  category: Clinical
  description: >
    Persistent pelvic pain after the acute episode, reported in 42% of women with
    endometrial M. genitalium in the PEACH substudy.
  phenotype_term:
    preferred_term: Chronic pain
    term:
      id: HP:0012532
      label: Chronic pain
    temporality: CHRONIC
  frequency: FREQUENT
  evidence:
  - reference: PMID:18445635
    reference_title: "Failure of cefoxitin and doxycycline to eradicate endometrial Mycoplasma genitalium and the consequence for clinical cure of pelvic inflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rates of sequelae, including infertility (22%), recurrent PID (31%) and chronic pelvic pain (42%), were high among women testing positive for endometrial M genitalium at baseline."
    explanation: >
      42% chronic pelvic pain falls in the FREQUENT band. Note the scope condition: this is
      the M. genitalium-positive subgroup of a treated trial cohort, not all PID.
- name: Hydrosalpinx
  category: Clinical
  description: >
    Distended, fluid-filled fallopian tube, the imaged structural consequence of distal
    tubal occlusion after salpingitis.
  phenotype_term:
    preferred_term: Hydrosalpinx
    term:
      id: HP:6000146
      label: Hydrosalpinx
  evidence:
  - reference: PMID:11779608
    reference_title: "Chlamydial heat shock protein 60--specific T cells in inflamed salpingeal tissue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients with tubal factor infertility who underwent elective salpingectomy because of hydrosalpinges."
    explanation: >
      Documents hydrosalpinx as the tubal lesion in women with post-inflammatory tubal
      factor infertility.
- name: Fever
  category: Clinical
  description: >
    Oral temperature above 38.3 degrees C, one of the CDC additional criteria that raise
    the specificity of an otherwise nonspecific clinical picture. Absent in a substantial
    fraction of cases, which is why it is not among the minimum criteria.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One or more of the following additional criteria can be used to enhance the specificity of the minimum clinical criteria and support a PID diagnosis:"
    explanation: >
      Introduces the CDC additional-criteria list whose first entry is oral temperature
      >38.3 degrees C, establishing fever as a recognized supporting finding. No frequency
      band is assigned because the guideline states only that the criterion raises
      specificity, not how often fever is present.
- name: Abnormal vaginal discharge
  category: Clinical
  description: >
    Mucopurulent cervical discharge, a sign of the lower genital tract inflammation that
    accompanies most PID and one of the CDC additional criteria.
  phenotype_term:
    preferred_term: Abnormal cervical mucopurulent discharge
    term:
      id: HP:0034269
      label: Abnormal vaginal discharge
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of women with PID have either mucopurulent cervical discharge or evidence of WBCs on a microscopic evaluation of a saline preparation of vaginal fluid"
    explanation: >
      Establishes discharge as a majority finding. No frequency band is assigned because
      the claim is a disjunction with wet-prep leukocytes, so it does not license a
      majority rate for discharge on its own.
- name: Cervicitis
  category: Clinical
  description: >
    Inflammation of the cervix, evidenced by mucopurulent discharge and cervical friability.
    It is the lower genital tract lesion contiguous with the ascending infection and, when
    present alongside a minimum criterion, increases diagnostic specificity.
  phenotype_term:
    preferred_term: Cervicitis
    term:
      id: HP:0030160
      label: Cervicitis
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the presence of signs of lower genital tract inflammation (predominance of leukocytes in vaginal secretions, cervical discharge, or cervical friability), in addition to one of the three minimum criteria, increases the specificity of the diagnosis."
    explanation: >
      Names the signs that constitute cervicitis and their diagnostic role in PID.
- name: Dyspareunia
  category: Clinical
  description: >
    Pain with intercourse, one of the mild or nonspecific symptoms whose under-recognition
    the CDC identifies as a reason episodes of PID go undiagnosed.
  phenotype_term:
    preferred_term: Dyspareunia
    term:
      id: HP:0030016
      label: Dyspareunia
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient or the health care provider do not recognize the implications of mild or nonspecific symptoms or signs (e.g., abnormal bleeding, dyspareunia, and vaginal discharge)."
    explanation: >
      Lists dyspareunia among the presenting symptoms of PID. No frequency band is assigned
      because the guideline characterizes these as mild or nonspecific without quantifying
      them.
- name: Abnormal uterine bleeding
  category: Clinical
  description: >
    Intermenstrual or postcoital bleeding, a nonspecific presenting sign of PID that is
    frequently not attributed to upper genital tract infection.
  phenotype_term:
    preferred_term: Abnormal uterine bleeding
    term:
      id: HP:0034263
      label: Abnormal vaginal bleeding
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient or the health care provider do not recognize the implications of mild or nonspecific symptoms or signs (e.g., abnormal bleeding, dyspareunia, and vaginal discharge)."
    explanation: >
      Lists abnormal bleeding among the presenting symptoms of PID. No frequency band is
      assigned for the same reason as dyspareunia.

biochemical:
- name: Elevated Erythrocyte Sedimentation Rate
  presence: Present
  context: Supportive laboratory testing in suspected PID
  notes: >-
    Nonspecific acute-phase marker. Elevation is one of the CDC additional criteria that
    raise the specificity of a clinical PID diagnosis; a normal value does not exclude PID,
    which is why it is supportive rather than diagnostic.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One or more of the following additional criteria can be used to enhance the specificity of the minimum clinical criteria and support a PID diagnosis:"
    explanation: >-
      Introduces the CDC additional-criteria list, which includes elevated erythrocyte
      sedimentation rate as a supportive laboratory finding.
- name: Elevated C-Reactive Protein
  presence: Present
  context: Supportive laboratory testing in suspected PID
  notes: >-
    Acute-phase reactant. Like the ESR it is supportive rather than diagnostic, and is
    listed among the CDC additional criteria.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One or more of the following additional criteria can be used to enhance the specificity of the minimum clinical criteria and support a PID diagnosis:"
    explanation: >-
      Introduces the CDC additional-criteria list, which includes elevated C-reactive
      protein as a supportive laboratory finding.
- name: Vaginal Fluid Leukocytes On Saline Microscopy
  presence: Present
  context: Bedside wet-prep microscopy in suspected PID
  notes: >-
    Abundant white blood cells on a wet preparation of vaginal fluid. This is the highest
    yield bedside laboratory finding in PID: the CDC states that a normal cervical
    discharge together with an absence of wet-prep leukocytes makes the diagnosis unlikely,
    giving the test substantial negative predictive value.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If the cervical discharge appears normal and no WBCs are observed on the wet prep of vaginal fluid, a PID diagnosis is unlikely, and alternative causes of pain should be considered."
    explanation: >-
      Establishes the negative predictive value of absent vaginal fluid leukocytes, the
      basis for curating this as a diagnostic marker rather than a phenotype.

diagnosis:
- name: Clinical diagnosis with a low empiric-treatment threshold
  description: >
    PID is diagnosed on clinical suspicion. Because the clinical picture is nonspecific
    and the cost of missing the diagnosis is irreversible tubal damage, guidelines set the
    treatment threshold deliberately low: pelvic or lower abdominal pain plus cervical
    motion, uterine or adnexal tenderness in a woman at risk is sufficient. The
    consequence is that the diagnosed population is not the same as the true-disease
    population in either direction, which is the main obstacle to interpreting PID
    epidemiology.
  evidence:
  - reference: PMID:31524362
    reference_title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis is made primarily on clinical suspicion, and empiric treatment is recommended in sexually active young women or women at risk for sexually transmitted infections who have unexplained lower abdominal or pelvic pain and cervical motion, uterine, or adnexal tenderness on examination."
    explanation: >
      States the clinical criteria and the empiric-treatment threshold.
  - reference: PMID:34396398
    reference_title: "A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical diagnosis of PID is nonspecific, creating an urgent need to develop noninvasive tests to diagnose PID."
    explanation: >
      Establishes the nonspecificity that makes the low threshold necessary and the
      diagnosed population imprecise.

treatments:
- name: Ceftriaxone
  description: >
    Third-generation cephalosporin given as a single intramuscular dose, the
    gonococcal-coverage component of the recommended regimen. It is not the component that
    addresses chlamydial upper tract infection, because beta-lactams do not reach the
    intracellular compartment where chlamydia replicates.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antibiotic Therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
    therapeutic_agent:
    - preferred_term: ceftriaxone
      term:
        id: CHEBI:29007
        label: ceftriaxone
  target_mechanisms:
  - target: Ascension to the Upper Genital Tract
    treatment_effect: INHIBITS
    description: >
      Eradicating gonococcal infection of the upper tract removes the organism driving the
      inflammatory response.
    evidence:
    - reference: PMID:34292926
      reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Ceftriaxone has better coverage against N. gonorrhoeae."
      explanation: >
        Names ceftriaxone specifically as the component of the CDC PID regimen selected for
        gonococcal coverage, which is the basis for assigning it the INHIBITS edge against
        gonococcal ascension rather than the doxycycline/metronidazole backbone.
    - reference: PMID:34292926
      reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All regimens used to treat PID should also be effective against N. gonorrhoeae and C. trachomatis because negative endocervical screening for these organisms does not rule out upper genital tract infection."
      explanation: >
        Establishes that the therapeutic target of the anti-gonococcal component is upper
        genital tract infection, not merely the endocervical reservoir — the mechanism this
        edge asserts.
  evidence:
  - reference: PMID:31524362
    reference_title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild to moderate disease can be treated in an outpatient setting with a single intramuscular injection of a recommended cephalosporin followed by oral doxycycline for 14 days."
    explanation: >
      Establishes the single-dose intramuscular cephalosporin as the first component of
      outpatient therapy.

- name: Doxycycline
  description: >
    Tetracycline given orally for 14 days, the component of the regimen that reaches
    intracellular chlamydia. Its role in this entry is not merely additive coverage: it is
    the drug that satisfies the cell-penetrance requirement created by the intracellular
    niche, which is why the regimen cannot be simplified to a cephalosporin alone.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antibiotic Therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
  target_mechanisms:
  - target: Requirement for a Cell-Penetrant Antimicrobial
    treatment_effect: INHIBITS
    description: >
      Doxycycline accumulates intracellularly and is therefore the agent that answers the
      cell-penetrance constraint this node encodes.
    evidence:
    - reference: PMID:31524362
      reference_title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mild to moderate disease can be treated in an outpatient setting with a single intramuscular injection of a recommended cephalosporin followed by oral doxycycline for 14 days."
      explanation: >
        Establishes doxycycline as the recommended partner agent in the regimen.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Doxycycline 100 mg orally 2 times/day for 14 days with metronidazole 500 mg orally 2 times/day for 14 days"
    explanation: >
      Gives the recommended dose and duration.
  notes: >
    Doxycycline is a ribosome-targeting antibiotic, so this treatment is a candidate
    conformer for bacterial_protein_synthesis_inhibition. No such conformance is claimed
    here because the entry carries no evidence-bearing node for the ribosomal target
    itself; see the curation note at the end of this file.

- name: Metronidazole
  description: >
    Nitroimidazole with anaerobic activity, added to ceftriaxone and doxycycline for 14
    days. Its inclusion is the therapeutic expression of the bacterial-vaginosis arm of
    this entry's pathograph: a randomised placebo-controlled trial showed it reduces
    endometrial anaerobes, reduces cervical M. genitalium and reduces pelvic tenderness,
    and it moved from conditional to routine in the 2021 guidelines on that basis.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antibiotic Therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
    therapeutic_agent:
    - preferred_term: metronidazole
      term:
        id: CHEBI:6909
        label: metronidazole
  target_mechanisms:
  - target: Loss of Vaginal Lactobacillus Dominance
    treatment_effect: INHIBITS
    description: >
      Metronidazole suppresses the anaerobic consortium that constitutes the
      bacterial-vaginosis entry route and that is recoverable from the endometrium.
    evidence:
    - reference: PMID:32052831
      reference_title: "A Randomized Controlled Trial of Ceftriaxone and Doxycycline, With or Without Metronidazole, for the Treatment of Acute Pelvic Inflammatory Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At 30 days following treatment, anaerobic organisms were less frequently recovered from the endometrium in women treated with metronidazole than placebo (8% vs 21%, P < .05) and cervical Mycoplasma genitalium was reduced (4% vs 14%, P < .05)."
      explanation: >
        Randomised, placebo-controlled evidence that metronidazole acts on exactly the
        organisms this node represents, measured in the endometrium.
  evidence:
  - reference: PMID:32052831
    reference_title: "A Randomized Controlled Trial of Ceftriaxone and Doxycycline, With or Without Metronidazole, for the Treatment of Acute Pelvic Inflammatory Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In women treated for acute PID, the addition of metronidazole to ceftriaxone and doxycycline was well tolerated and resulted in reduced endometrial anaerobes, decreased M. genitalium, and reduced pelvic tenderness compared to ceftriaxone and doxycycline."
    explanation: >
      The trial's own conclusion, which is the basis for routine addition of metronidazole.

- name: Outpatient versus inpatient management
  description: >
    Route-of-care decision rather than a distinct drug. The PEACH randomised trial found
    no difference in reproductive outcomes between inpatient intravenous therapy and
    outpatient intramuscular-plus-oral therapy for mild-to-moderate disease, which is why
    outpatient management is the default; hospitalization is reserved for pregnancy,
    severe illness, outpatient failure, tubo-ovarian abscess, or an unexcluded surgical
    emergency.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:12015517
    reference_title: "Effectiveness of inpatient and outpatient treatment strategies for women with pelvic inflammatory disease: results from the Pelvic Inflammatory Disease Evaluation and Clinical Health (PEACH) Randomized Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among women with mild-to-moderate pelvic inflammatory disease, there was no difference in reproductive outcomes between women randomized to inpatient treatment and those randomized to outpatient treatment."
    explanation: >
      Randomised evidence that the route of care does not change reproductive outcome in
      mild-to-moderate disease.
  - reference: PMID:31524362
    reference_title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hospitalization for parenteral antibiotics is recommended in patients who are pregnant or severely ill, in whom outpatient treatment has failed, those with tubo-ovarian abscess, or if surgical emergencies cannot be excluded."
    explanation: >
      Gives the exceptions that override the outpatient default.
  notes: >
    The PEACH result is easy to over-read. It reports no difference in outcome between
    treatment settings; it does not report that outcomes were good. Pregnancy rates were
    approximately 42% in both arms over a mean 35 months of follow-up.

- name: Chlamydia screening of at-risk women
  description: >
    Primary prevention rather than treatment of established disease. Identifying and
    treating cervical chlamydial infection before it ascends is the only intervention in
    this entry that acts upstream of irreversible tubal damage; a randomised trial roughly
    halved PID incidence.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Lower Genital Tract Infection and Cervical Colonization
    treatment_effect: INHIBITS
    description: >
      Screening detects and treats the cervical reservoir before ascent occurs, removing
      the initiating node rather than mitigating its consequences.
    evidence:
    - reference: PMID:8614421
      reference_title: "Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At the end of the follow-up period, there had been 9 verified cases of pelvic inflammatory disease among the women in the screening group and 33 cases among the women receiving usual care (relative risk, 0.44; 95 percent confidence interval, 0.20 to 0.90)."
      explanation: >
        Randomised evidence that treating the cervical reservoir prevents downstream PID.
  evidence:
  - reference: PMID:8614421
    reference_title: "Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A strategy of identifying, testing, and treating women at increased risk for cervical chlamydial infection was associated with a reduced incidence of pelvic inflammatory disease."
    explanation: >
      The trial's conclusion supporting screening as PID prevention.
  notes: >
    Curated with treatment_term Supportive Care because NCIT's clinical-action branch has
    no screening term that both fits a population screening programme and validates against
    the TreatmentTerm enum; the free-text name carries the specificity.

- name: Sex partner treatment
  description: >
    Treatment of sexual partners, including expedited partner therapy where legally
    permitted. It prevents reinfection, which matters here because the tubal lesion is
    cumulative in episode number.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31524362
    reference_title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sex partner treatment is recommended; expedited partner treatment is recommended where legal."
    explanation: >
      States the recommendation and its legal qualifier.

- name: Drainage or surgery for tubo-ovarian abscess
  description: >
    Source control when a tubo-ovarian abscess does not respond to parenteral antibiotics.
    Reserved for medical failure; it addresses the acute-severity branch of the pathograph
    and does nothing for the fibrotic sequelae.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Drainage
    term:
      id: NCIT:C50434
      label: Drainage
  target_mechanisms:
  - target: Tubo-ovarian Abscess and Pelvic Peritonitis
    treatment_effect: INHIBITS
    description: >
      Drainage removes the walled-off collection that antibiotics alone may not sterilize.
  evidence:
  - reference: PMID:31524362
    reference_title: "Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hospitalization for parenteral antibiotics is recommended in patients who are pregnant or severely ill, in whom outpatient treatment has failed, those with tubo-ovarian abscess, or if surgical emergencies cannot be excluded."
    explanation: >
      Supports tubo-ovarian abscess as an indication for escalation of care. Marked PARTIAL
      because this source states the hospitalization indication rather than the drainage
      procedure itself.

differential_diagnoses:
- name: Acute appendicitis
  description: >
    The classic and most dangerous alternative. The reflex of treating any young woman
    with abdominal pain as PID until proven otherwise has produced ruptured appendices.
  evidence:
  - reference: PMID:3537321
    reference_title: "Tubo-ovarian abscess: pathogenesis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This view is dangerous and should be challenged because it has resulted in episodes of ruptured appendix, death from ruptured ectopic pregnancies, and serious morbidity from delayed diagnoses of such entities as diverticulitis and endometriosis."
    explanation: >
      Names the misdiagnoses that follow from treating PID as the default diagnosis.
- name: Ruptured ectopic pregnancy
  description: >
    Shares the pain and adnexal tenderness, is immediately life-threatening, and is also a
    downstream consequence of prior PID — so a history of PID raises rather than lowers
    the prior for this alternative.
  evidence:
  - reference: PMID:3537321
    reference_title: "Tubo-ovarian abscess: pathogenesis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This view is dangerous and should be challenged because it has resulted in episodes of ruptured appendix, death from ruptured ectopic pregnancies, and serious morbidity from delayed diagnoses of such entities as diverticulitis and endometriosis."
    explanation: >
      Names death from ruptured ectopic pregnancy among the consequences of the PID
      default.
- name: Endometriosis
  description: >
    Overlaps on chronic pelvic pain and dyspareunia; distinguished by the cyclical pattern
    and by laparoscopic appearance.
  evidence:
  - reference: PMID:3537321
    reference_title: "Tubo-ovarian abscess: pathogenesis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This view is dangerous and should be challenged because it has resulted in episodes of ruptured appendix, death from ruptured ectopic pregnancies, and serious morbidity from delayed diagnoses of such entities as diverticulitis and endometriosis."
    explanation: >
      Names endometriosis among the diagnoses delayed by the PID default.
- name: Diverticulitis
  description: >
    Left-sided pelvic pain with fever, misclassified as PID when the diagnosis is assumed
    from sex and symptom location.
  evidence:
  - reference: PMID:3537321
    reference_title: "Tubo-ovarian abscess: pathogenesis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This view is dangerous and should be challenged because it has resulted in episodes of ruptured appendix, death from ruptured ectopic pregnancies, and serious morbidity from delayed diagnoses of such entities as diverticulitis and endometriosis."
    explanation: >
      Names diverticulitis among the diagnoses delayed by the PID default.

discussions:
- discussion_id: pid_subclinical_treatment_failure
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    Why does treating gonococcal, chlamydial and bacterial-vaginosis infection fail to
    restore fertility in women who already have subclinical endometritis, and what would
    an intervention that does work have to target?
  attaches_to:
  - pathophysiology#Subclinical Upper Genital Tract Inflammation
  - pathophysiology#Tubal Factor Infertility
  rationale: >
    This is the most consequential gap in the entry, and it is awkward for the whole
    prevention model. In a prospective cohort, women who had biopsy-defined subclinical PID
    at enrollment had a 40% lower subsequent pregnancy incidence even though they received
    treatment for their gonococcal, chlamydial or bacterial-vaginosis infection — while
    women with those same infections but without subclinical PID were not at increased
    risk. The dividing line is therefore the presence of upper tract inflammation, not the
    presence of the organism, and antimicrobial therapy directed at the organism does not
    undo it. Either the damage is already fixed by the time endometritis is detectable, or
    the inflammation persists after the organism is cleared. The two possibilities imply
    completely different interventions — earlier detection versus anti-inflammatory
    adjunctive therapy — and nothing in the current evidence distinguishes them.
  evidence:
  - reference: PMID:22678036
    reference_title: "Subclinical pelvic inflammatory disease and infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subclinical PID decreases subsequent fertility despite provision of treatment for sexually transmitted diseases."
    explanation: >
      States the failure of organism-directed treatment to prevent the fertility loss.
  - reference: PMID:22678036
    reference_title: "Subclinical pelvic inflammatory disease and infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Women with Neisseria gonorrhoeae or Chlamydia trachomatis, in the absence of subclinical PID, were not at increased risk for infertility."
    explanation: >
      Establishes that upper tract inflammation, rather than the organism, is the
      discriminating variable — the observation that makes this a mechanistic gap rather
      than a treatment-adherence problem.
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The optimal treatment regimen and long-term outcome of early treatment of women with subclinical PID are unknown."
    explanation: >
      The CDC guideline states this gap in its own words, so the discussion rests on a
      quoted source rather than on inference from the cohort data alone.
  proposed_experiments:
  - experiment_id: pid_endometritis_resolution_cohort
    name: Serial endometrial sampling after treatment of subclinical PID
    description: >
      Follow women with biopsy-confirmed subclinical endometritis through and after
      standard antimicrobial therapy with repeat endometrial biopsy and organism testing,
      and relate persistence of histologic inflammation (as opposed to persistence of the
      organism) to subsequent tubal patency and fertility. A dissociation — organism
      cleared, inflammation persisting, fertility reduced — would identify the residual
      inflammation as the target and justify testing an anti-inflammatory adjunct.
    experiment_type:
      preferred_term: prospective cohort with serial endometrial biopsy
    would_support:
    - pathophysiology#Subclinical Upper Genital Tract Inflammation

- discussion_id: pid_etiology_regimen_mismatch
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >
    If fewer than half of PID cases involve gonorrhoea or chlamydia, is a regimen designed
    around those two organisms still the right one?
  attaches_to:
  - pathophysiology#Lower Genital Tract Infection and Cervical Colonization
  - pathophysiology#Loss of Vaginal Lactobacillus Dominance
  rationale: >
    The recommended regimen was built around N. gonorrhoeae and C. trachomatis, but
    contemporary series find neither organism in more than half of diagnosed cases, with
    M. genitalium, respiratory pathogens and the bacterial-vaginosis consortium accounting
    for a substantial share. The metronidazole trial is the first piece of that gap to be
    closed with randomised evidence, and it closed it in the direction of the anaerobes.
    The M. genitalium share remains uncovered: a PEACH substudy showed that cefoxitin plus
    doxycycline does not eradicate endometrial M. genitalium and that carriage predicted
    short-term treatment failure. Whether that translates into a change of regimen depends
    on evidence that does not yet exist, since no trial has shown that treating
    M. genitalium prevents PID or its sequelae.
  evidence:
  - reference: PMID:34396398
    reference_title: "A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent studies of women with PID have reported that fewer than half of women receiving a diagnosis of PID have gonococcal or chlamydial infection, while Mycoplasma genitalium, respiratory pathogens, and the constellation of bacteria associated with bacterial vaginosis may account for a substantial fraction of PID cases."
    explanation: >
      Quantifies the mismatch between the regimen's design and the observed etiology.
  - reference: PMID:18445635
    reference_title: "Failure of cefoxitin and doxycycline to eradicate endometrial Mycoplasma genitalium and the consequence for clinical cure of pelvic inflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cefoxitin and doxycycline, a Centers for Disease Control and Prevention recommended PID treatment regimen, is ineffective for the treatment of M genitalium upper genital tract infection."
    explanation: >
      Demonstrates the specific coverage failure for M. genitalium.
  - reference: PMID:18192788
    reference_title: "Evidence for a role of Mycoplasma genitalium in pelvic inflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PCR studies have demonstrated that M. genitalium is associated with clinically suspected pelvic inflammatory disease, acute endometritis, and adnexitis, independent of gonococcal and chlamydial infection."
    explanation: >
      Establishes that the M. genitalium association is independent of the two classical
      organisms, so it is not explained by co-infection.

- discussion_id: pid_chronic_pain_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    What mechanism connects a resolved episode of upper genital tract inflammation to
    persistent pelvic pain years later?
  attaches_to:
  - pathophysiology#Chronic Pelvic Pain
  rationale: >
    Chronic pelvic pain is one of the three canonical sequelae of PID and is the most
    common long-term complaint, yet unlike infertility and ectopic pregnancy it has no
    structural correlate in this pathograph. Post-inflammatory adhesions are the usual
    explanation, but the pain frequently persists in women whose acute infection was
    treated and cleared, and no cited source here demonstrates the adhesion-to-pain step.
    The edge from tubal fibrosis to chronic pain in this entry is deliberately typed
    INDIRECT_UNKNOWN_INTERMEDIATES for that reason: naming adhesions as the mechanism
    would assert more than the cited literature supports.
  evidence:
  - reference: PMID:18445635
    reference_title: "Failure of cefoxitin and doxycycline to eradicate endometrial Mycoplasma genitalium and the consequence for clinical cure of pelvic inflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rates of sequelae, including infertility (22%), recurrent PID (31%) and chronic pelvic pain (42%), were high among women testing positive for endometrial M genitalium at baseline."
    explanation: >
      Documents the high rate of chronic pelvic pain in a treated trial cohort, showing the
      sequela is common despite therapy.

notes: >
  Curation notes and deliberate omissions.

  Module conformance. Two nodes conform to intracellular_pathogen_persistence, which is
  the honest fit: both classical pathogens occupy an intracellular niche, and that is why
  the regimen pairs a cephalosporin with a cell-penetrant tetracycline. Two further
  conformances were considered and withheld. First, fibrotic_response — the entry does
  reach tubal fibrosis, but the only cited support for the matrix arm is a review sentence
  saying the metalloproteinase-regulated matrix "may also be modified" by chlamydial
  infection, and there is no evidence here for a mesenchymal-cell-activation node, which
  is the module's load-bearing step. Claiming conformance on the strength of the word
  "fibrosis" appearing in both places would be name matching, not mechanism matching.
  Second, bacterial_protein_synthesis_inhibition and
  bacterial_cell_wall_synthesis_inhibition — doxycycline and ceftriaxone are textbook
  conformers by drug class, but this entry carries no evidence-bearing pathophysiology
  node for the ribosome or for penicillin-binding-protein cross-linking, and adding target
  nodes purely to host a conformance edge would invert the intended direction of the
  pattern. Both remain good follow-ups for a curator willing to source the target-level
  evidence.

  Ontology gap. The Ectopic pregnancy phenotype is left unbound because HP:0031456 sits
  under HP:0002686 Pregnancy history, outside the HP:0000118 root the PhenotypeTerm enum
  is reachable from. This is a fifth instance of gap 3 in issue #7837, after HP:0003826
  Stillbirth, HP:0009800 Maternal diabetes and HP:0100602 Preeclampsia.

  Denominators. The 4.4% lifetime figure is self-reported clinical diagnosis among
  sexually experienced US women aged 18-44, not a measure of upper genital tract
  infection; given that clinical diagnosis is both insensitive and nonspecific, it should
  not be read as disease prevalence in either direction. Separately, the 42%
  chronic-pelvic-pain and 22% infertility rates cited from PMID:18445635 are for the
  M. genitalium-positive subgroup of a treated trial cohort, not for PID generally, and
  are curated with that scope condition stated in the explanations.

  Relationship to neighbouring entries. Ectopic_Pregnancy models the implantation event
  and already carries Chlamydia trachomatis tubal infection as an antecedent; this entry
  models the inflammatory disease that produces the damaged tube, and the two meet at the
  Ectopic Implantation node. Gonorrhea and Chorioamnionitis are the organism-level and
  pregnancy-context neighbours respectively. No attempt is made here to duplicate the
  organism-level biology curated in those entries.

  Sources. No deep-research provider report was generated for this entry; it was built
  from PubMed searches and the cached references directly, and that is stated rather than
  left to be inferred. Two causes named in the reviews — respiratory pathogens and genital
  tuberculosis — are real causes of PID in some settings but are not modelled, because no
  node in this pathograph would be specific to them.

📚

References & Deep Research

References

PMID:34396413

Pelvic Inflammatory Disease Due to Neisseria gonorrhoeae and Chlamydia trachomatis: Immune Evasion Mechanisms and Pathogenic Disease Pathways.

2 findings

PID follows ascension of sexually transmitted pathogens from the lower genital tract, and both classical pathogens survive intracellularly and actively evade innate and adaptive immunity.

Endometrial transcriptional profiling in women with PID shows myeloid, cell death and innate inflammatory pathway activation alongside suppressed T-cell activation.

PMID:34396398

A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease.

2 findings

Fewer than half of women diagnosed with PID have gonococcal or chlamydial infection; M. genitalium, respiratory pathogens and bacterial-vaginosis-associated bacteria account for a substantial fraction.

The clinical diagnosis is nonspecific and there is no validated noninvasive test.

PMID:25592078

Pathogenesis of fallopian tube damage caused by Chlamydia trachomatis infections.

1 finding

Permanent tubal damage in chlamydial infection is a consequence of the host innate and adaptive immune response to ongoing or repeated infection rather than of direct microbial cytotoxicity.

PMID:1411832

Pelvic inflammatory disease and fertility. A cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results.

1 finding

The reference cohort quantifying tubal factor infertility and ectopic pregnancy after laparoscopically confirmed PID, and the dose-response with episode number and severity.

PMID:31524362

Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention.

1 finding

Contemporary clinical review covering the empiric-treatment threshold, the outpatient cephalosporin-plus-doxycycline regimen, indications for hospitalization, and partner treatment.

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