Abstract
Introduction:
Bubonic plague classically manifests as a painful, swollen superficial lymph node (bubo) that is readily apparent on physical examination. However, patients occasionally present with buboes formed in deep lymph nodes, which are difficult to detect and can lead to delays in diagnosis and treatment. To better characterize this phenomenon, we conducted a review of the published literature to identify reports of occult buboes among patients with plague.
Methods:
Articles were identified from two sources: a systematic review on plague treatment, and a search of the PubMed Central database. Articles were eligible if they described a patient with plague who had (1) no evidence of lymphadenopathy on examination; and (2) at least one bubo discovered during surgery or autopsy.
Results:
Six patients with occult buboes were identified among 5120 articles screened. The majority were male (n = 4/6) and three were <15 years of age. Fever (n = 6/6), leukocytosis (n = 5/6), and abdominal pain or distention (n = 4/6) were the most common signs and symptoms. Initial diagnoses included other bacterial infections, appendicitis, or acute abdomen. Four patients received at least one antimicrobial effective against Yersinia pestis; however, some experienced delayed treatment due to late diagnosis of plague. Occult buboes were discovered in retroperitoneal (n = 2), inguinal/femoral (n = 2), mesenteric (n = 2), axillary (n = 1), and mediastinal (n = 1) regions. Four of the six patients died.
Conclusions:
Patients with occult buboes experienced delays in the diagnosis of plague and a high fatality rate. Clinicians in plague-endemic areas should consider the presence of occult buboes among patients with compatible symptoms and exposure history.
Introduction
Plague is a potentially fatal zoonotic disease caused by the nonmotile, gram-negative coccobacillus Yersinia pestis (Bennett et al. 2015). The three most common clinical manifestations of infection are bubonic, pneumonic, and septicemic plague. While most notorious for causing deadly pandemics centuries ago, Y. pestis continues to cause hundreds of cases of plague annually across the globe and is a pathogen of concern for potential bioterrorist attacks (Bertherat 2016; Select agents and toxins list 2021). All forms of plague are treatable if antimicrobials effective against Y. pestis are administered, although survival rates are highest when treatment is initiated early in the course of infection (Nelson et al. 2020).
Bubonic plague is the predominant manifestation of the disease (Dennis et al. 1999). Characterized by the development of an enlarged tender lymph node known as a bubo, bubonic plague owes its name to the Greek word “boubōn,” meaning “groin” or “swelling in the groin” (Definition of bubo 2020). Although buboes can potentially develop within any lymph node in the body, they most commonly occur in inguinal/femoral, axillary, and cervical lymph nodes (Nelson et al. 2020). Buboes have also been occasionally described in epitrochlear (Sharpe et al. 1974, Butler et al. 1976, Welty et al. 1976), supraclavicular (Laforce et al. 1971, Butler et al. 1976, Neal 1989), and submaxillary (Huang and Chu 1946, Wagle and Bedarkar 1948) locations. Intra-abdominal and retroperitoneal buboes have been documented rarely in the literature (Coura et al. 1967, Reed et al. 1970).
Because buboes typically present as painful swellings in superficial lymph nodes, they are often easily appreciable to the patient or health care provider, thereby aiding in the diagnosis of bubonic plague. However, buboes that form in deep lymph nodes are likely to remain unnoticed. In the absence of a frank bubo, the differential diagnosis for ill patients with fever and other nonspecific manifestations of plague is much broader, and clinicians may not suspect plague, delaying effective treatment.
Occult buboes have been reported sporadically among patients with plague; however, a systematic assessment of occult buboes has not been performed to our knowledge. To better characterize this condition, we conducted a review of the published literature to identify reports of patients who did not have apparent buboes on physical examination but were ultimately diagnosed with plague after autopsy or surgical procedure. Improved awareness of the potential for occult buboes to occur can facilitate the timely diagnosis of plague and tailoring of treatment regimens to include appropriate antimicrobials effective against Y. pestis.
Methods
Articles were primarily identified from a systematic review on the antimicrobial treatment of plague, for which the literature search strategy was limited to antimicrobial treatment terms (Nelson et al. 2020). Detailed information on the methods used in that systematic review has been published elsewhere (Nelson et al. 2020). During the systematic review, articles describing patients with potential occult buboes were flagged for later assessment and potential inclusion in this case series. For the purposes of this review, a hand search of the PubMed Central (PMC) database was also performed by one reviewer (S.F.D.) using the following search terms: [(“plague” or “pestis”) and (“bubo” or “buboes”)].
Articles were deemed eligible by a single reviewer (S.F.D.) if they described a patient with plague who had (1) no evidence of lymphadenopathy on physical examination and was not diagnosed with bubonic plague on initial presentation; and (2) at least one bubo discovered during either a surgical procedure or autopsy, prompting the diagnosis of bubonic plague. For cases described in multiple articles, information from each article was compared and abstracted. Any discrepancies between articles were discussed and adjudicated by reviewers (C.A.N. and S.F.D.).
Results
A total of 3531 articles were screened from the plague treatment systematic review by Nelson et al. (2020). The PMC search yielded an additional 1589 articles that were screened for potential eligibility.
Eleven articles describing six cases were eligible for inclusion in this case series (Table 1). Cases were reported between 1898 and 1997. Of the five cases for which timing was known, all occurred between May and August. All but one case-patients were from the United States; the remaining case-patient was from India. The majority (n = 4/6, 66.7%) of cases were male. Among the five cases with age reported, the median age was 14 years (range 8–71 years), with three (60%) <15 years of age.
Characteristics of Six Patients with Occult Buboes
Time from symptom onset to initiation of an antimicrobial effective against Yersinia pestis; ranges are reported when the exact day of initiation was not provided.
Confirmed: (1) isolation of Y. pestis from a clinical specimen with confirmatory bacteriophage testing, or (2) a fourfold change in serologic titer. Probable: (1) isolation or direct detection of Y. pestis in a clinical specimen using direct fluorescent antibody testing, polymerase chain reaction, or other means without confirmatory bacteriophage testing, or (2) single positive serologic titer, or (3) less than fourfold change in serologic titer (Nelson et al. 2020).
Year of publication was used because year of case occurrence was not reported.
Although not explicitly stated, the timing of initiation of chloramphenicol was presumed to be during this range of days.
N/A, not applicable.
The most common symptoms reported were fever (n = 6/6, 100%), abdominal pain or distention (n = 4/6, 66.7%), vomiting (n = 3/6, 50%), and malaise (n = 3/6, 50%). Five patients had leukocytosis (median: 29.2 × 109/L; range: 12.3–52.7 × 109/L). The presence of thrombocytopenia or anemia was not reported in any articles.
For all patients, plague was not a suspected diagnosis before the patient's surgery or death. Alternative initial diagnoses included pneumonia (n = 1), gram-negative sepsis (n = 1), streptococcal pharyngitis (n = 1), acute appendicitis (n = 1), and acute abdomen (n = 1). For one case, the admission diagnosis was not recorded.
Five of the six patients were treated with antimicrobials, although some experienced delayed treatment due to their late diagnosis of plague. Four patients were administered at least one antimicrobial effective against Y. pestis; these included chloramphenicol (n = 2), streptomycin (n = 1), gentamicin (n = 1), and doxycycline (n = 1). One patient, who was diagnosed with streptococcal pharyngitis, received only penicillin (case 4). Penicillin is not considered an effective antimicrobial for treating plague (Nelson et al. 2021).
Two (33.3%) patients underwent exploratory laparotomy as part of their clinical workup. Both surgical procedures revealed the presence of a previously unrecognized retroperitoneal bubo. The remaining four (66.7%) patients died, and buboes were subsequently discovered on autopsy. Two (50%) of the four autopsies revealed buboes in the inguinal/femoral region, two (50%) in the mesenteric region, one (25%) in the axillary region, and one (25%) in the mediastinal region.
Case summaries
Case 1
An adult male was hospitalized in 1898 with fever, cough, and chest pain (Prall 1898). No buboes were noted on physical examination, and he was diagnosed with pneumonia. The patient died suddenly later that day. On autopsy “the inguinal glands and the glands on the external iliac vein showed the characteristic plague lesions.”
Case 2
In 1961, a 38-year-old male was admitted for fever, chest pain, severe malaise, and diaphoresis (Leland 1961, Mengis 1962). He had hunted in several wooded areas about 15 miles east of Santa Fe and herded sheep on the day before becoming ill. On the day of admission, he developed cyanosis, severe dyspnea, and abdominal distention. No lymphadenopathy was noted, and plague was not suspected. Diffuse bilateral pneumonitis was identified on chest radiograph. His white blood cell count was 13.2 × 109/L with 72% neutrophils. Antimicrobial treatment consisted of penicillin and chloramphenicol. Early the next day, the patient went into septic shock and died. Autopsy showed “hyperplasia of the lymph nodes of the mediastinum and mesentery, with an increase in large mononuclear cells and reticulum cells” (Mengis 1962).
Case 3
A 14-year-old male was hospitalized in August 1965 with fever, headache, anorexia, vomiting, and altered mental status (Zobel et al. 1965, Collins 1967). No lymphadenopathy was noted on physical examination; chest radiograph and lumbar puncture were unremarkable. His white blood cell count was 12.3 × 109/L with a left shift. The following day he developed respiratory distress, a productive cough, and bloody sputum. Repeat chest radiograph revealed bilateral pulmonary infiltration. He was treated with streptomycin and penicillin but died later that day after cardiorespiratory arrest. Autopsy showed “enlarged and hemorrhagic lymph nodes in the…axilla” (Zobel et al. 1965). Further investigation revealed that the patient had direct contact with prairie dogs, and a prairie dog die-off was reported in the vicinity of his home.
Case 4
In June 1974, a 13-year-old female was evaluated at an outpatient clinic for fever, headache, and malaise (Zalma et al. 1974, von Reyn et al. 1977, Jones et al. 1979, Becker et al. 1987). On physical examination, tonsillar exudate was noted. Chest radiograph was normal. The patient was treated with penicillin and instructed to return the following day. Upon return, she reported vomiting along with persistent fever and malaise. Laboratory test results revealed a white blood cell count of 52.7 × 109/L with 48% polymorphonuclear neutrophils. Petechiae and nuchal rigidity were not present on examination.
She died from cardiorespiratory arrest before the completion of a comprehensive workup. Autopsy demonstrated “massive hemorrhagic lymphadenopathy of the left inguinal femoral iliac nodes and marked congestion of the left adrenal medulla” (Jones et al. 1979) and “enlarged mesenteric nodes and hemorrhagic lymph nodes in the left femoral region” (Becker et al. 1987).
Case 5
An 8-year-old male was admitted to the hospital with fever and malaise (Moreno et al. 1987). The following day he developed abdominal tenderness, and acute appendicitis was suspected. Laboratory findings were significant for a white blood cell count of 29.2 × 109/L with 30% polymorphonuclear neutrophils. Exploratory laparotomy revealed a normal appendix, “easily reducible sigmoid volvulus, marked hepatosplenomegaly and numerous enlarged retroperitoneal lymph nodes.” 67Ga-citrate scintigraphy also demonstrated abdominal lymphadenopathy. Postoperatively, he developed respiratory distress, disseminated intravascular coagulation, and acute renal failure. Chloramphenicol and cefotaxime were administered.
Three weeks after the initiation of treatment, during which time antimicrobials were discontinued and later reinstituted, the patient's illness finally resolved and he was discharged without complications.
Case 6
In June 1997, a 71-year-old female presented with fever and abdominal pain and was prescribed antimicrobials (the specific antimicrobial treatment initially administered was not reported) (Smith et al. 1998). Two days later she returned to the hospital with vomiting, diarrhea, and hallucinations in addition to persistent fever and abdominal pain. Her white blood cell count was 30.0 × 109/L with 30% bands. Before an exploratory laparotomy, cephalosporin and metronidazole were initiated. During the procedure, “a large retroperitoneal mass was identified. Further exploration revealed it to be bilateral periaortic adenopathy. Several large nodes in the left peritoneum were removed and revealed acute necrotizing lymphadenitis with abscess formation.”
Postoperatively, intravenous gentamicin and doxycycline were added to her treatment regimen. Ten days after the initiation of antimicrobials, her symptoms resolved and she was discharged. Evidence of woodrat huts was found near her home, as well as squirrel burrows under her home's foundation. A recent disappearance of ground squirrels had been reported in the area a few weeks before her illness onset, suggesting a die-off.
Discussion
This review describes six cases of bubonic plague among patients who were initially thought to have other conditions; their diagnosis of plague came only after discovery of an occult bubo during either a surgical procedure or autopsy. All but two of the cases were fatal. Although occult buboes are currently thought to occur in a small subset of all plague cases, increased awareness of their occurrence will assist in a more timely and accurate diagnosis of plague, as well as appropriate treatment.
The six patients included in this review were mostly male, and three were younger than 15 years. The finding of a higher proportion of males is consistent with the current epidemiology of plague around the world; however, the pediatric population tends to make up less than half of cases worldwide (Kugeler et al. 2015, Nelson et al. 2020). Differences in immune response and difficulties with articulating specific symptoms may have contributed to a high proportion of patients younger than 15 years with occult buboes being identified in this review.
Bubonic plague is most commonly caused by the bite of an infected flea, and the location of bubo formation generally depends on the location of inoculation. Interestingly, all but one patient in this review developed a bubo in the middle or lower regions of the body. It is possible that Y. pestis inoculation via a lower extremity or trunk is more likely to cause an occult bubo by seeding deep inguinal, retroperitoneal, or mesenteric lymph nodes. Occult buboes might also result from infection via the gastrointestinal tract or a flea bite on the abdomen (Goldman and Schafer 2019).
Fever, abdominal pain or distention, and leukocytosis were the most common manifestations reported before a surgical procedure or autopsy. In the absence of apparent buboes, the presence of these three manifestations together may lead clinicians to suspect a variety of etiologies unrelated to plague, including acute appendicitis, enteric or foodborne illnesses, and sepsis. Interestingly, all four patients who had either retroperitoneal, mediastinal, or mesenteric occult buboes in this review experienced abdominal pain or distention, as well as leukocytosis. This suggests that, in the setting of a potential exposure to Y. pestis, the occurrence of these two signs without an appreciable bubo may indicate the presence of occult buboes.
Of note, the two patients with retroperitoneal buboes were the only two to survive in this review; however, the reasons for this are unknown. It is possible that the signs and symptoms of retroperitoneal buboes prompted exploratory laparotomy and discovery of the buboes. These two cases also occurred the most recently and, as a result, may have had better access to more effective antimicrobials and medical care. Nonetheless, it is difficult to interpret any associations found among this small number of patients.
All patients in this review had occult buboes discovered after either a surgical procedure or autopsy. It is therefore reasonable to assume that more instances of occult buboes have occurred but have ultimately remained unrecognized in the absence of a laparotomy, imaging, or autopsy. It is also plausible that a portion of patients diagnosed with primary septicemic plague initially developed occult buboes but were classified as primary septicemic plague as a result of their buboes remaining unnoticed.
There are limitations of this review worth mentioning. First, the included data are derived from only case reports and case series, which are observational and often low-quality sources of data known for their potential biases. Second, some case reports lacked relevant information, particularly for variables related to possible exposures to Y. pestis and the initial clinical workup of patients. Third, our hand search of PMC used only “bubo” or “buboes” as search terms and may have consequently missed articles describing cases of occult buboes that used different terminology, such as “glands” or “lymphadenopathy.” Lastly, one case included in this review was clinically diagnosed but did not have any laboratory testing performed for Y. pestis; therefore, it may not have been a true case of plague.
Conclusion
Without appropriate and timely antimicrobial treatment, plague often results in death. While the current incidence of occult buboes is unknown, their presence might result in a higher fatality rate than other forms of plague due to their tendency to remain undiagnosed and therefore not properly treated. In plague-endemic areas, health care providers who evaluate patients with abdominal pain or distention, fever, and leukocytosis plus a compatible exposure history should consider plague with an occult bubo as a potential diagnosis. Enhanced recognition that occult buboes can occur could help improve patient survival among those afflicted with this elusive manifestation of plague.
Footnotes
Authors' Contributions
S.F.D. conducted data abstraction, analysis and interpretation of results, and article writing and editing; K.M.C.: conducted data abstraction, and article writing and article editing; C.A.N.: conceived the study design, performed analysis and interpretation of results, and article writing and editing.
Author Disclosure Statement
No conflicting financial interests exist.
Funding Information
No funding was received for this article.