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Infectious Disease and Microbiology – Bartonellosis (Oroya Fever/Verruga Peruana)
Bartonellosis is an infection caused by Bartonella bacilliformis, transmitted by sandflies of the genus Phlebotomus. It occurs in endemic areas and presents in two distinct clinical forms. Nonimmune individuals typically develop an acute febrile illness known as Oroya fever, characterized by profound hemolytic anemia. After recovery from the acute phase, a chronic cutaneous form called verruga peruana may develop, featuring angioproliferative skin lesions that resemble those seen in bacillary angiomatosis caused by other Bartonella species.
The disease is endemic to the Andean river valleys at altitudes between 600 and 2,500 meters in Peru, Ecuador, and Colombia. Oroya fever most commonly affects tourists or visitors who lack prior immunity, whereas verruga peruana is more frequently seen in the native population. Rare imported cases have been reported outside endemic regions. Risk factors include residence in or travel to endemic areas and exposure to the sandfly vector. Prevention focuses on vector control measures such as indoor and outdoor insecticide spraying, use of insect repellents, and bed nets.
Pathophysiologically, B. bacilliformis invades erythrocytes and endothelial cells. The bacteria multiply within intracellular vacuoles inside red blood cells, which are subsequently destroyed by the reticuloendothelial system, resulting in severe hemolytic anemia. The organism is a small, gram-negative bacillus closely related to Bartonella quintana.
The incubation period of Oroya fever averages about three weeks but can extend up to 100 days. The acute illness may begin gradually with low-grade fever, malaise, headache, and anorexia, or abruptly with high fever, chills, diaphoresis, altered mental status, and rapidly progressive anemia. Patients may experience dyspnea, chest discomfort, myalgias, arthralgias, and in severe cases, delirium or coma. Anasarca indicates a poor prognosis. During the convalescent phase, fever subsides and anemia improves.
Physical examination in Oroya fever reveals high fever, signs of profound anemia, generalized nontender lymphadenopathy, and occasionally thrombocytopenic purpura. Splenomegaly is uncommon and may suggest concurrent infection.
Verruga peruana develops weeks to months after recovery from the acute phase. Lesions appear in crops and may be miliary (1–4 mm papular erythematous lesions), nodular, or larger “mular” lesions exceeding 5 mm in diameter. They are typically bright red, bleed easily, and may involve skin, mucous membranes, or internal organs. Lesions are generally nontender unless secondarily infected and may be present at different stages simultaneously.
Diagnosis in the acute phase is made by identifying numerous bacteria attached to red blood cells on Giemsa- or Wright-stained peripheral blood smears or by positive blood or bone marrow cultures. Peripheral smear may also reveal macrocytosis, poikilocytosis, Howell–Jolly bodies, nucleated red blood cells, and immature myeloid cells. Profound anemia with a negative Coombs’ test is typical. In subacute cases, smears may initially be negative, and blood cultures are required. In the chronic phase, organisms can be demonstrated in cultures from skin lesions or bone marrow. Serologic tests such as ELISA or indirect immunofluorescence can support the diagnosis. Skin biopsy may show increased angiogenesis and characteristic endothelial inclusions (Rocha-Lima inclusions).
The acute phase must be differentiated from other endemic febrile illnesses such as malaria, typhoid fever, and leptospirosis. Verruga lesions resemble bacillary angiomatosis, Kaposi’s sarcoma, and certain neoplasms; epidemiologic context is a key diagnostic clue.
Treatment of Oroya fever consists of chloramphenicol (500 mg orally or intravenously every 6 hours) combined with a second antimicrobial, preferably a beta-lactam such as penicillin, for 14 days. Chloramphenicol also provides coverage against salmonellosis, a common secondary infection. Doxycycline is an alternative agent, while fluoroquinolones are generally not recommended due to resistance. Verruga peruana is treated with rifampin (10 mg/kg daily, maximum 600 mg daily) for 10–14 days. Streptomycin is a second-line option. Supportive care, including blood transfusion for severe anemia, is essential in the acute phase. Large or secondarily infected skin lesions may require surgical excision.
Patients with Oroya fever typically require inpatient management, whereas those with verruga peruana can often be managed as outpatients. Monitoring during the acute phase should include hydration status, complete blood counts, and surveillance for secondary infections such as salmonellosis, malaria, or tuberculosis.
Untreated Oroya fever carries a mortality rate of 50–88%. With appropriate therapy, fever usually resolves within 24 hours, though bacteremia may persist longer. Complications include secondary bacterial infections during convalescence and ulceration or bleeding of verruga lesions.
Bartonellosis is an infection caused by Bartonella bacilliformis, transmitted by sandflies of the genus Phlebotomus. It occurs in endemic areas and presents in two distinct clinical forms. Nonimmune individuals typically develop an acute febrile illness known as Oroya fever, characterized by profound hemolytic anemia. After recovery from the acute phase, a chronic cutaneous form called verruga peruana may develop, featuring angioproliferative skin lesions that resemble those seen in bacillary angiomatosis caused by other Bartonella species.
The disease is endemic to the Andean river valleys at altitudes between 600 and 2,500 meters in Peru, Ecuador, and Colombia. Oroya fever most commonly affects tourists or visitors who lack prior immunity, whereas verruga peruana is more frequently seen in the native population. Rare imported cases have been reported outside endemic regions. Risk factors include residence in or travel to endemic areas and exposure to the sandfly vector. Prevention focuses on vector control measures such as indoor and outdoor insecticide spraying, use of insect repellents, and bed nets.
Pathophysiologically, B. bacilliformis invades erythrocytes and endothelial cells. The bacteria multiply within intracellular vacuoles inside red blood cells, which are subsequently destroyed by the reticuloendothelial system, resulting in severe hemolytic anemia. The organism is a small, gram-negative bacillus closely related to Bartonella quintana.
The incubation period of Oroya fever averages about three weeks but can extend up to 100 days. The acute illness may begin gradually with low-grade fever, malaise, headache, and anorexia, or abruptly with high fever, chills, diaphoresis, altered mental status, and rapidly progressive anemia. Patients may experience dyspnea, chest discomfort, myalgias, arthralgias, and in severe cases, delirium or coma. Anasarca indicates a poor prognosis. During the convalescent phase, fever subsides and anemia improves.
Physical examination in Oroya fever reveals high fever, signs of profound anemia, generalized nontender lymphadenopathy, and occasionally thrombocytopenic purpura. Splenomegaly is uncommon and may suggest concurrent infection.
Verruga peruana develops weeks to months after recovery from the acute phase. Lesions appear in crops and may be miliary (1–4 mm papular erythematous lesions), nodular, or larger “mular” lesions exceeding 5 mm in diameter. They are typically bright red, bleed easily, and may involve skin, mucous membranes, or internal organs. Lesions are generally nontender unless secondarily infected and may be present at different stages simultaneously.
Diagnosis in the acute phase is made by identifying numerous bacteria attached to red blood cells on Giemsa- or Wright-stained peripheral blood smears or by positive blood or bone marrow cultures. Peripheral smear may also reveal macrocytosis, poikilocytosis, Howell–Jolly bodies, nucleated red blood cells, and immature myeloid cells. Profound anemia with a negative Coombs’ test is typical. In subacute cases, smears may initially be negative, and blood cultures are required. In the chronic phase, organisms can be demonstrated in cultures from skin lesions or bone marrow. Serologic tests such as ELISA or indirect immunofluorescence can support the diagnosis. Skin biopsy may show increased angiogenesis and characteristic endothelial inclusions (Rocha-Lima inclusions).
The acute phase must be differentiated from other endemic febrile illnesses such as malaria, typhoid fever, and leptospirosis. Verruga lesions resemble bacillary angiomatosis, Kaposi’s sarcoma, and certain neoplasms; epidemiologic context is a key diagnostic clue.
Treatment of Oroya fever consists of chloramphenicol (500 mg orally or intravenously every 6 hours) combined with a second antimicrobial, preferably a beta-lactam such as penicillin, for 14 days. Chloramphenicol also provides coverage against salmonellosis, a common secondary infection. Doxycycline is an alternative agent, while fluoroquinolones are generally not recommended due to resistance. Verruga peruana is treated with rifampin (10 mg/kg daily, maximum 600 mg daily) for 10–14 days. Streptomycin is a second-line option. Supportive care, including blood transfusion for severe anemia, is essential in the acute phase. Large or secondarily infected skin lesions may require surgical excision.
Patients with Oroya fever typically require inpatient management, whereas those with verruga peruana can often be managed as outpatients. Monitoring during the acute phase should include hydration status, complete blood counts, and surveillance for secondary infections such as salmonellosis, malaria, or tuberculosis.
Untreated Oroya fever carries a mortality rate of 50–88%. With appropriate therapy, fever usually resolves within 24 hours, though bacteremia may persist longer. Complications include secondary bacterial infections during convalescence and ulceration or bleeding of verruga lesions.
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Infectious Disease and Microbiology – Balanitis
Balanitis refers to inflammation and/or infection of the glans penis, while balanoposthitis involves both the glans and the foreskin. Infectious causes are common and may result from fungal, bacterial, viral, or parasitic pathogens. Sexual exposure plays an important role in transmission, particularly in men whose partners have Candida vaginitis. In young boys, balanitis may occur in association with diaper dermatitis.
Risk factors include being uncircumcised, diabetes mellitus (especially newly diagnosed diabetes), immunodeficiency, poor hygiene, use of broad-spectrum antibiotics, and increasing age in the case of Candida colonization. Circumcision and proper genital hygiene significantly reduce the risk. Treatment of sexual partners is important when Candida or Trichomonas infection is identified.
Infectious etiologies include Candida species (most common), Trichomonas species, anaerobic bacteria such as Bacteroides and Gardnerella vaginalis, Chlamydia, Neisseria gonorrhoeae, human papillomavirus (HPV), herpes simplex virus (HSV), Treponema pallidum, Mycoplasma, Mycobacterium (including Bacillus Calmette–Guérin), group A and B streptococci, Staphylococcus aureus, Borrelia burgdorferi, and Entamoeba histolytica.
Patients typically present with pain, tenderness, erythema, pruritus, edema, erosions, and sometimes pustules on the glans penis. Anaerobic infections may produce a characteristic foul odor.
Diagnosis is largely clinical but may be supported by laboratory testing. Fungal preparations often reveal Candida. Direct impression onto CHROMagar Candida medium has been shown to provide a higher yield than swab sampling. Wet mount examination may detect Trichomonas or Gardnerella. Urethral discharge should be tested for sexually transmitted infections. Serologic or culture testing for HIV, HPV, and HSV may be indicated based on risk factors. Blood glucose testing is recommended to evaluate for underlying diabetes mellitus.
The differential diagnosis includes numerous noninfectious conditions such as irritant dermatitis, trauma, contact dermatitis, lichen sclerosus, lichen planus, Zoon’s balanitis, erythroplasia of Queyrat, pemphigus, pemphigoid, Bowen’s disease, leukoplakia, fixed drug eruption, psoriasis (particularly inverse psoriasis), Paget’s disease, nummular eczema, scabies, and squamous cell carcinoma.
Management begins with good hygiene, including gentle washing of the glans after foreskin retraction. Candida balanitis is typically treated with topical imidazole antifungal agents, and 1% hydrocortisone cream may be added for symptomatic relief. Severe cases may require oral fluconazole. Trichomonas infection responds to metronidazole, and sexual partners should be treated simultaneously. Anaerobic infections may be managed with oral metronidazole, oral amoxicillin–clavulanate, or topical clindamycin cream.
Patients should be monitored for recurrence and evaluated for underlying diabetes if not previously diagnosed. Complications include phimosis, paraphimosis, fissuring of the prepuce, and scarring.
Balanitis refers to inflammation and/or infection of the glans penis, while balanoposthitis involves both the glans and the foreskin. Infectious causes are common and may result from fungal, bacterial, viral, or parasitic pathogens. Sexual exposure plays an important role in transmission, particularly in men whose partners have Candida vaginitis. In young boys, balanitis may occur in association with diaper dermatitis.
Risk factors include being uncircumcised, diabetes mellitus (especially newly diagnosed diabetes), immunodeficiency, poor hygiene, use of broad-spectrum antibiotics, and increasing age in the case of Candida colonization. Circumcision and proper genital hygiene significantly reduce the risk. Treatment of sexual partners is important when Candida or Trichomonas infection is identified.
Infectious etiologies include Candida species (most common), Trichomonas species, anaerobic bacteria such as Bacteroides and Gardnerella vaginalis, Chlamydia, Neisseria gonorrhoeae, human papillomavirus (HPV), herpes simplex virus (HSV), Treponema pallidum, Mycoplasma, Mycobacterium (including Bacillus Calmette–Guérin), group A and B streptococci, Staphylococcus aureus, Borrelia burgdorferi, and Entamoeba histolytica.
Patients typically present with pain, tenderness, erythema, pruritus, edema, erosions, and sometimes pustules on the glans penis. Anaerobic infections may produce a characteristic foul odor.
Diagnosis is largely clinical but may be supported by laboratory testing. Fungal preparations often reveal Candida. Direct impression onto CHROMagar Candida medium has been shown to provide a higher yield than swab sampling. Wet mount examination may detect Trichomonas or Gardnerella. Urethral discharge should be tested for sexually transmitted infections. Serologic or culture testing for HIV, HPV, and HSV may be indicated based on risk factors. Blood glucose testing is recommended to evaluate for underlying diabetes mellitus.
The differential diagnosis includes numerous noninfectious conditions such as irritant dermatitis, trauma, contact dermatitis, lichen sclerosus, lichen planus, Zoon’s balanitis, erythroplasia of Queyrat, pemphigus, pemphigoid, Bowen’s disease, leukoplakia, fixed drug eruption, psoriasis (particularly inverse psoriasis), Paget’s disease, nummular eczema, scabies, and squamous cell carcinoma.
Management begins with good hygiene, including gentle washing of the glans after foreskin retraction. Candida balanitis is typically treated with topical imidazole antifungal agents, and 1% hydrocortisone cream may be added for symptomatic relief. Severe cases may require oral fluconazole. Trichomonas infection responds to metronidazole, and sexual partners should be treated simultaneously. Anaerobic infections may be managed with oral metronidazole, oral amoxicillin–clavulanate, or topical clindamycin cream.
Patients should be monitored for recurrence and evaluated for underlying diabetes if not previously diagnosed. Complications include phimosis, paraphimosis, fissuring of the prepuce, and scarring.
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Infectious Diseases and Microbiology: Postoperative Fever
Basics
Description
Postoperative fever is defined as a body temperature above 38°C (100.4°F) occurring after an invasive procedure. It is classified by timing: immediate (during surgery or within hours), acute (within the first postoperative week), subacute (1–4 weeks after surgery), and delayed (more than one month postoperatively). Most cases result from the inflammatory response to surgery and resolve spontaneously, but fever may signal a serious complication. Evaluation requires careful history, physical examination, and appropriate laboratory and imaging studies, including cultures and Gram stains when indicated. Early postoperative fever is frequently noninfectious; however, fever persisting beyond 96 hours is more likely infectious. Consider that patients may have been incubating community-acquired infection preoperatively. New or persistent fever beyond four days strongly suggests ongoing pathology or a new complication. Surgical wounds, catheter insertion sites, and all dressings must be inspected, and recent interventions such as blood transfusions reviewed.
Epidemiology
Drug fever is the most common noninfectious cause of postoperative fever, most often linked to antimicrobials and heparin. Pneumonia is a common cause after cardiac surgery and occurs in more than 5% of such patients. Sternal wound infections after cardiothoracic surgery occur in up to 5%, typically around postoperative day seven. Postoperative aspergillosis after cardiothoracic procedures carries very high mortality. Fever alone is a poor predictor of infection, with low sensitivity. Postsurgical mediastinitis has high mortality. In obstetrics and gynecology, bacterial vaginosis may increase postoperative infection risk.
General Prevention
Aggressive pulmonary hygiene, including incentive spirometry and mobilization, reduces pulmonary complications such as atelectasis.
Etiology
Common infectious causes include urinary tract infection, pneumonia, sinusitis, suppurative thrombophlebitis, catheter-related infections, and Clostridioides difficile–associated diarrhea. Noninfectious causes include deep venous thrombosis, pulmonary embolism, subarachnoid hemorrhage, gout, and fat embolism. Surgical site infections are uncommon within the first 1–3 days except for aggressive pathogens such as group A streptococci or clostridia, which can present early. Atelectasis is frequently blamed but likely coincidental rather than causal. Other serious causes include transplant rejection. Drug-induced fever is most often associated with beta-lactams, antiepileptics, and heparin. Inflammatory states such as acute myocardial infarction, pancreatitis, or acute respiratory distress syndrome may produce fever without infection. Endocrine emergencies such as adrenal insufficiency or thyrotoxicosis may also present with fever.
Diagnosis
Physical Examination
Drug fever lacks specific features and usually develops days after medication exposure; rash and eosinophilia are uncommon. Malignant hyperthermia typically occurs intraoperatively but may be delayed up to 24 hours and is associated with agents such as succinylcholine or volatile anesthetics. Neuroleptic malignant syndrome is associated with antipsychotics, particularly haloperidol. Withdrawal syndromes from alcohol, opioids, barbiturates, or benzodiazepines may cause fever hours to days after admission, and prior substance use history may not be readily available.
Diagnostic Tests and Interpretation
Laboratory Studies
Urinalysis and urine culture are recommended in patients with indwelling catheters longer than 72 hours. Procalcitonin has uncertain value in distinguishing bacterial causes of postoperative fever.
Imaging
Duplex ultrasonography with Doppler should be considered for new extremity swelling suggestive of deep venous thrombosis. Routine chest radiography is not required within the first 72 postoperative hours if fever is the only indication.
Diagnostic Procedures/Other
Wound swab cultures are rarely useful unless there is clear clinical evidence of infection. Suspected deep intraabdominal abscess may require imaging and, if inconclusive, surgical exploration.
Treatment
Medications
Antibiotics are generally not indicated for early postoperative fever without evidence of infection. Critically ill patients or those with hemodynamic instability should receive empiric broad-spectrum antibiotics after thorough evaluation, but therapy should be discontinued after 48 hours if no infectious source is identified. Atelectasis management includes coughing exercises, incentive spirometry, chest physiotherapy, beta-2 agonists, intermittent positive-pressure breathing, and nebulization. Empiric antifungal therapy is not recommended initially.
Ongoing Care and Follow-Up
Drug fever is diagnosed by exclusion when other causes are ruled out. Surgical wounds and invasive device sites must be repeatedly examined for signs of infection.
Complications
Postoperative infections increase morbidity and mortality, may lead to sepsis, impair wound healing, and cause respiratory failure and other serious outcomes.
Basics
Description
Postoperative fever is defined as a body temperature above 38°C (100.4°F) occurring after an invasive procedure. It is classified by timing: immediate (during surgery or within hours), acute (within the first postoperative week), subacute (1–4 weeks after surgery), and delayed (more than one month postoperatively). Most cases result from the inflammatory response to surgery and resolve spontaneously, but fever may signal a serious complication. Evaluation requires careful history, physical examination, and appropriate laboratory and imaging studies, including cultures and Gram stains when indicated. Early postoperative fever is frequently noninfectious; however, fever persisting beyond 96 hours is more likely infectious. Consider that patients may have been incubating community-acquired infection preoperatively. New or persistent fever beyond four days strongly suggests ongoing pathology or a new complication. Surgical wounds, catheter insertion sites, and all dressings must be inspected, and recent interventions such as blood transfusions reviewed.
Epidemiology
Drug fever is the most common noninfectious cause of postoperative fever, most often linked to antimicrobials and heparin. Pneumonia is a common cause after cardiac surgery and occurs in more than 5% of such patients. Sternal wound infections after cardiothoracic surgery occur in up to 5%, typically around postoperative day seven. Postoperative aspergillosis after cardiothoracic procedures carries very high mortality. Fever alone is a poor predictor of infection, with low sensitivity. Postsurgical mediastinitis has high mortality. In obstetrics and gynecology, bacterial vaginosis may increase postoperative infection risk.
General Prevention
Aggressive pulmonary hygiene, including incentive spirometry and mobilization, reduces pulmonary complications such as atelectasis.
Etiology
Common infectious causes include urinary tract infection, pneumonia, sinusitis, suppurative thrombophlebitis, catheter-related infections, and Clostridioides difficile–associated diarrhea. Noninfectious causes include deep venous thrombosis, pulmonary embolism, subarachnoid hemorrhage, gout, and fat embolism. Surgical site infections are uncommon within the first 1–3 days except for aggressive pathogens such as group A streptococci or clostridia, which can present early. Atelectasis is frequently blamed but likely coincidental rather than causal. Other serious causes include transplant rejection. Drug-induced fever is most often associated with beta-lactams, antiepileptics, and heparin. Inflammatory states such as acute myocardial infarction, pancreatitis, or acute respiratory distress syndrome may produce fever without infection. Endocrine emergencies such as adrenal insufficiency or thyrotoxicosis may also present with fever.
Diagnosis
Physical Examination
Drug fever lacks specific features and usually develops days after medication exposure; rash and eosinophilia are uncommon. Malignant hyperthermia typically occurs intraoperatively but may be delayed up to 24 hours and is associated with agents such as succinylcholine or volatile anesthetics. Neuroleptic malignant syndrome is associated with antipsychotics, particularly haloperidol. Withdrawal syndromes from alcohol, opioids, barbiturates, or benzodiazepines may cause fever hours to days after admission, and prior substance use history may not be readily available.
Diagnostic Tests and Interpretation
Laboratory Studies
Urinalysis and urine culture are recommended in patients with indwelling catheters longer than 72 hours. Procalcitonin has uncertain value in distinguishing bacterial causes of postoperative fever.
Imaging
Duplex ultrasonography with Doppler should be considered for new extremity swelling suggestive of deep venous thrombosis. Routine chest radiography is not required within the first 72 postoperative hours if fever is the only indication.
Diagnostic Procedures/Other
Wound swab cultures are rarely useful unless there is clear clinical evidence of infection. Suspected deep intraabdominal abscess may require imaging and, if inconclusive, surgical exploration.
Treatment
Medications
Antibiotics are generally not indicated for early postoperative fever without evidence of infection. Critically ill patients or those with hemodynamic instability should receive empiric broad-spectrum antibiotics after thorough evaluation, but therapy should be discontinued after 48 hours if no infectious source is identified. Atelectasis management includes coughing exercises, incentive spirometry, chest physiotherapy, beta-2 agonists, intermittent positive-pressure breathing, and nebulization. Empiric antifungal therapy is not recommended initially.
Ongoing Care and Follow-Up
Drug fever is diagnosed by exclusion when other causes are ruled out. Surgical wounds and invasive device sites must be repeatedly examined for signs of infection.
Complications
Postoperative infections increase morbidity and mortality, may lead to sepsis, impair wound healing, and cause respiratory failure and other serious outcomes.
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Infectious Diseases and Microbiology: Sore Throat
Basics
Description
Sore throat refers to painful inflammation of the pharynx, typically worse with swallowing. Common infectious causes are covered elsewhere; the emphasis here is recognizing distinguishing clinical features and considering noninfectious etiologies.
Approach to the Patient
First assess for airway compromise and decide whether the illness is localized or part of a systemic process, most often viral. Clarify symptom type and duration and ask about hoarseness and fever. History should include sick contacts, oral–genital sexual exposure, recent weight loss, and other features suggesting noninfectious causes such as neoplasms. Findings that strongly support streptococcal pharyngitis include fever, marked tonsillar exudate and enlargement, tender anterior cervical nodes, myalgias, and supportive epidemiology such as age, season, and community colonization prevalence. Conjunctivitis points toward viral illness. When clinical and epidemiologic clues suggest gonococcal pharyngitis or diphtheria, use specific microbiologic techniques and begin appropriate therapy promptly. Differentiate laryngitis, croup, and other hoarseness syndromes from epiglottitis. The main practical distinction is group A streptococcal versus nonstreptococcal pharyngitis, confirmed by throat culture or rapid antigen testing.
Epidemiology
Most pharyngitis is viral, accounting for roughly 90% of adult cases and 70% of pediatric cases. Group A beta-hemolytic Streptococcus is more common in children than adults. Antibiotic prescribing is frequent in adults with pharyngitis. In outbreaks involving rheumatogenic strains, untreated group A streptococcal infection can be followed by acute rheumatic fever in a small but meaningful percentage. Lancefield groups C and G streptococci can cause syndromes similar to group A disease and are often opportunistic or healthcare-associated. Arcanobacterium hemolyticum is seen particularly in adolescents and young adults. Parainfluenza infection is most common in children.
General Prevention
Advise patients with streptococcal pharyngitis to avoid close contact with others, and counsel on safer sex practices to reduce sexually transmitted causes.
Etiology
Acute pharyngitis is most often viral, including rhinovirus, coronavirus, influenza A/B, and parainfluenza, and may involve broader respiratory tract symptoms. Acute laryngitis is usually viral and can be caused by rhinovirus, influenza, parainfluenza, coxsackievirus, adenovirus, or respiratory syncytial virus. Some viruses produce characteristic patterns, including herpangina from coxsackie A, infectious mononucleosis from Epstein–Barr virus or cytomegalovirus, HSV gingivostomatitis, and adenoviral pharyngoconjunctival fever. Primary HSV-1 can cause acute pharyngitis, and HSV-2 can cause similar illness after oral–genital exposure. Acute pharyngitis can occur during primary HIV infection. The key bacterial cause is group A Streptococcus, with additional causes including groups C and G streptococci, Arcanobacterium hemolyticum, Neisseria gonorrhoeae, Corynebacterium diphtheriae, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. Sore throat can also occur with systemic infections such as toxoplasmosis, plague, brucellosis, leptospirosis, secondary syphilis, Yersinia infections, and tularemia. Histoplasma and Blastomyces can cause laryngeal nodules with or without ulceration. Candida can cause sore throat with thrush in immunosuppressed patients or those with mucocutaneous candidiasis. West Nile virus can present as a febrile illness with malaise, headache, myalgias, rash, and occasional pharyngitis. Lemierre syndrome can present with sore throat. Deep neck infections include parapharyngeal abscess from spread of tonsillitis, pharyngitis with adenoid involvement, parotitis, mastoiditis, or periodontal infection, and retropharyngeal abscess from spread, lymphatic seeding, trauma, or cervical osteomyelitis extension. Acute necrotizing pharyngeal infections can cause foul breath, fever, and choking sensation, often associated with ulcerative gingivitis. Ludwig angina arises from dental infection near the third molar and causes rapidly spreading bilateral submandibular and sublingual cellulitis with swelling, pain, trismus, drooling, tongue displacement, and progressive dysphagia and sore throat that can lead to airway obstruction. PFAPA syndrome affects young children and causes periodic high fevers lasting several days with aphthous stomatitis, pharyngitis, and cervical adenitis, recurring at regular short intervals without other symptoms.
Diagnosis
Parapharyngeal space infection typically causes toxic appearance, fever, sore throat, dysphagia, and leukocytosis, with possible neck rigidity or contralateral torticollis; advanced disease can produce dyspnea and stridor. Acute necrotizing pharyngeal infection presents with swollen erythematous ulcerated tonsillar pillars covered by a gray membrane that peels easily and is often accompanied by lymphadenopathy. In infectious mononucleosis, pharyngitis is most prominent in the first two weeks. Herpangina presents with fever, sore throat, myalgias, and vesicles on the soft palate between the uvula and tonsils. Tuberculous laryngitis can cause mucosal hyperemia, thickening, nodules, and ulcerations.
Diagnostic Tests and Interpretation
Laboratory Studies
Throat culture is the reference standard for streptococcal diagnosis but takes 24–72 hours. Rapid antigen tests are highly specific but have variable sensitivity.
Imaging
Retropharyngeal infection may be suggested by lateral neck soft-tissue radiography, while CT or MRI best defines source and extent.
Diagnostic Procedures/Other
In suspected tuberculous laryngitis, biopsy may show granulomas with acid-fast bacilli, with cultures needed for confirmation and susceptibility testing.
Differential Diagnosis
Viral pharyngitis commonly includes sore throat with coryza and cough, an inflamed edematous pharynx, and usually no exudate, though adenovirus and mononucleosis can be exudative. Fever, tender anterior cervical nodes, erythematous pharynx with or without tonsillar enlargement or exudate, and absence of cough support streptococcal pharyngitis in children and adults. Mycoplasma-related sore throat typically occurs in young healthy patients with mild pharyngitis and prominent tracheobronchitis symptoms.
Treatment
Medications
Patients at high risk of complications from streptococcal infection, such as those with prior rheumatic carditis or valvular disease, should receive immediate antibiotics while awaiting culture confirmation. Parapharyngeal space infection management includes airway protection, operative drainage, and intravenous antibiotics targeting streptococci and oral anaerobes, using regimens such as penicillin plus metronidazole, cefoxitin, or ampicillin-sulbactam. For streptococcal pharyngitis, a single intramuscular dose of benzathine penicillin may be slightly more effective than oral penicillin VK and ensures adherence.
Ongoing Care and Follow-Up
Post-viral chronic fatigue syndrome can include fatigue, fever, sore throat, painful lymph nodes, myalgias, arthralgias, sleep disturbance, and headache. Appropriate treatment and monitoring of group A streptococcal infection aims to prevent nonsuppurative complications such as acute rheumatic fever and glomerulonephritis, reduce toxic complications and local suppurative spread, limit transmission, and shorten illness duration. Sore throat can also precede broader constitutional symptoms that culminate in viral encephalitis.
Complications
Peritonsillar abscess can follow untreated streptococcal pharyngitis and presents with unilateral swelling and erythema and uvular deviation. Parapharyngeal infections can lead to airway obstruction, aspiration after intraoral rupture, jugular vein thrombophlebitis with pulmonary emboli, carotid artery erosion, and mediastinitis.
Basics
Description
Sore throat refers to painful inflammation of the pharynx, typically worse with swallowing. Common infectious causes are covered elsewhere; the emphasis here is recognizing distinguishing clinical features and considering noninfectious etiologies.
Approach to the Patient
First assess for airway compromise and decide whether the illness is localized or part of a systemic process, most often viral. Clarify symptom type and duration and ask about hoarseness and fever. History should include sick contacts, oral–genital sexual exposure, recent weight loss, and other features suggesting noninfectious causes such as neoplasms. Findings that strongly support streptococcal pharyngitis include fever, marked tonsillar exudate and enlargement, tender anterior cervical nodes, myalgias, and supportive epidemiology such as age, season, and community colonization prevalence. Conjunctivitis points toward viral illness. When clinical and epidemiologic clues suggest gonococcal pharyngitis or diphtheria, use specific microbiologic techniques and begin appropriate therapy promptly. Differentiate laryngitis, croup, and other hoarseness syndromes from epiglottitis. The main practical distinction is group A streptococcal versus nonstreptococcal pharyngitis, confirmed by throat culture or rapid antigen testing.
Epidemiology
Most pharyngitis is viral, accounting for roughly 90% of adult cases and 70% of pediatric cases. Group A beta-hemolytic Streptococcus is more common in children than adults. Antibiotic prescribing is frequent in adults with pharyngitis. In outbreaks involving rheumatogenic strains, untreated group A streptococcal infection can be followed by acute rheumatic fever in a small but meaningful percentage. Lancefield groups C and G streptococci can cause syndromes similar to group A disease and are often opportunistic or healthcare-associated. Arcanobacterium hemolyticum is seen particularly in adolescents and young adults. Parainfluenza infection is most common in children.
General Prevention
Advise patients with streptococcal pharyngitis to avoid close contact with others, and counsel on safer sex practices to reduce sexually transmitted causes.
Etiology
Acute pharyngitis is most often viral, including rhinovirus, coronavirus, influenza A/B, and parainfluenza, and may involve broader respiratory tract symptoms. Acute laryngitis is usually viral and can be caused by rhinovirus, influenza, parainfluenza, coxsackievirus, adenovirus, or respiratory syncytial virus. Some viruses produce characteristic patterns, including herpangina from coxsackie A, infectious mononucleosis from Epstein–Barr virus or cytomegalovirus, HSV gingivostomatitis, and adenoviral pharyngoconjunctival fever. Primary HSV-1 can cause acute pharyngitis, and HSV-2 can cause similar illness after oral–genital exposure. Acute pharyngitis can occur during primary HIV infection. The key bacterial cause is group A Streptococcus, with additional causes including groups C and G streptococci, Arcanobacterium hemolyticum, Neisseria gonorrhoeae, Corynebacterium diphtheriae, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. Sore throat can also occur with systemic infections such as toxoplasmosis, plague, brucellosis, leptospirosis, secondary syphilis, Yersinia infections, and tularemia. Histoplasma and Blastomyces can cause laryngeal nodules with or without ulceration. Candida can cause sore throat with thrush in immunosuppressed patients or those with mucocutaneous candidiasis. West Nile virus can present as a febrile illness with malaise, headache, myalgias, rash, and occasional pharyngitis. Lemierre syndrome can present with sore throat. Deep neck infections include parapharyngeal abscess from spread of tonsillitis, pharyngitis with adenoid involvement, parotitis, mastoiditis, or periodontal infection, and retropharyngeal abscess from spread, lymphatic seeding, trauma, or cervical osteomyelitis extension. Acute necrotizing pharyngeal infections can cause foul breath, fever, and choking sensation, often associated with ulcerative gingivitis. Ludwig angina arises from dental infection near the third molar and causes rapidly spreading bilateral submandibular and sublingual cellulitis with swelling, pain, trismus, drooling, tongue displacement, and progressive dysphagia and sore throat that can lead to airway obstruction. PFAPA syndrome affects young children and causes periodic high fevers lasting several days with aphthous stomatitis, pharyngitis, and cervical adenitis, recurring at regular short intervals without other symptoms.
Diagnosis
Parapharyngeal space infection typically causes toxic appearance, fever, sore throat, dysphagia, and leukocytosis, with possible neck rigidity or contralateral torticollis; advanced disease can produce dyspnea and stridor. Acute necrotizing pharyngeal infection presents with swollen erythematous ulcerated tonsillar pillars covered by a gray membrane that peels easily and is often accompanied by lymphadenopathy. In infectious mononucleosis, pharyngitis is most prominent in the first two weeks. Herpangina presents with fever, sore throat, myalgias, and vesicles on the soft palate between the uvula and tonsils. Tuberculous laryngitis can cause mucosal hyperemia, thickening, nodules, and ulcerations.
Diagnostic Tests and Interpretation
Laboratory Studies
Throat culture is the reference standard for streptococcal diagnosis but takes 24–72 hours. Rapid antigen tests are highly specific but have variable sensitivity.
Imaging
Retropharyngeal infection may be suggested by lateral neck soft-tissue radiography, while CT or MRI best defines source and extent.
Diagnostic Procedures/Other
In suspected tuberculous laryngitis, biopsy may show granulomas with acid-fast bacilli, with cultures needed for confirmation and susceptibility testing.
Differential Diagnosis
Viral pharyngitis commonly includes sore throat with coryza and cough, an inflamed edematous pharynx, and usually no exudate, though adenovirus and mononucleosis can be exudative. Fever, tender anterior cervical nodes, erythematous pharynx with or without tonsillar enlargement or exudate, and absence of cough support streptococcal pharyngitis in children and adults. Mycoplasma-related sore throat typically occurs in young healthy patients with mild pharyngitis and prominent tracheobronchitis symptoms.
Treatment
Medications
Patients at high risk of complications from streptococcal infection, such as those with prior rheumatic carditis or valvular disease, should receive immediate antibiotics while awaiting culture confirmation. Parapharyngeal space infection management includes airway protection, operative drainage, and intravenous antibiotics targeting streptococci and oral anaerobes, using regimens such as penicillin plus metronidazole, cefoxitin, or ampicillin-sulbactam. For streptococcal pharyngitis, a single intramuscular dose of benzathine penicillin may be slightly more effective than oral penicillin VK and ensures adherence.
Ongoing Care and Follow-Up
Post-viral chronic fatigue syndrome can include fatigue, fever, sore throat, painful lymph nodes, myalgias, arthralgias, sleep disturbance, and headache. Appropriate treatment and monitoring of group A streptococcal infection aims to prevent nonsuppurative complications such as acute rheumatic fever and glomerulonephritis, reduce toxic complications and local suppurative spread, limit transmission, and shorten illness duration. Sore throat can also precede broader constitutional symptoms that culminate in viral encephalitis.
Complications
Peritonsillar abscess can follow untreated streptococcal pharyngitis and presents with unilateral swelling and erythema and uvular deviation. Parapharyngeal infections can lead to airway obstruction, aspiration after intraoral rupture, jugular vein thrombophlebitis with pulmonary emboli, carotid artery erosion, and mediastinitis.
- Published on
Infectious Diseases and Microbiology: Red Eye
Basics
Description
Red eye may result from sight-threatening conditions such as uveitis, endophthalmitis, acute angle-closure glaucoma, or scleritis, which typically produce ciliary injection. More commonly, redness is due to conjunctival hyperemia associated with conjunctivitis, keratitis, dry eye disease, foreign body irritation (including contact lenses), blepharitis, or environmental irritants. Ocular trauma may cause subconjunctival hemorrhage. Not all causes are infectious. Uveitis involves intraocular inflammation and may be anterior, posterior, or pan-uveitis. Endophthalmitis is a severe intraocular infection involving the vitreous cavity. Acute angle-closure glaucoma is an ophthalmic emergency caused by obstruction of aqueous outflow and elevated intraocular pressure. Episcleritis affects superficial scleral tissues, while scleritis is a deeper, more severe inflammatory process that may occur with keratitis or uveitis. Conjunctivitis is the most common cause of red eye and usually includes discharge. Keratitis primarily affects the cornea.
Epidemiology
Primary acute angle closure occurs more frequently in Asian populations than in Caucasians. Incidence rates for conjunctivitis, keratitis, and uveitis vary and are addressed in their respective discussions.
Risk Factors
Risk factors for angle-closure glaucoma include advanced age, hyperopia, cataract, female sex, prior angle closure in the fellow eye, and Asian ethnicity; prophylactic laser iridotomy is often performed in the unaffected eye. Contact lens use increases the risk of bacterial keratitis. Subconjunctival hemorrhage may occur spontaneously or with bleeding disorders, minor trauma, or increased venous pressure from coughing or sneezing. Autoimmune connective tissue disorders are associated with ocular inflammation, and uveitis may be an initial manifestation.
General Prevention
Proper contact lens hygiene reduces infectious and inflammatory complications. Screening with gonioscopy and preventive laser iridotomy can prevent acute angle closure in high-risk individuals.
Pathophysiology
Ciliary injection involves deeper vascular branches and indicates inflammation of the cornea, iris, ciliary body, or sclera. Conjunctival injection is superficial, mobile with the conjunctiva, and improves with topical vasoconstrictors. Acute angle closure usually results from pupillary block, causing pressure differential between the posterior and anterior chambers, forward bowing of the iris, and obstruction of aqueous outflow through the trabecular meshwork.
Etiology
Conjunctivitis, keratitis, uveitis, and endophthalmitis have infectious and noninfectious causes. Acute angle-closure glaucoma and subconjunctival hemorrhage are noninfectious. Episcleritis is usually idiopathic, though immunologic reactions to herpes simplex or varicella zoster may occur. Scleritis is rarely infectious but may result from systemic infections or extension from keratitis; reported pathogens include fungi (Aspergillus, Fusarium), herpes viruses, mycobacteria, Nocardia, Pseudomonas, Proteus (after scleral buckle procedures), syphilis, leprosy, Lyme disease, and tuberculosis.
Commonly Associated Conditions
Endophthalmitis most commonly follows intraocular surgery. Contact lens wear strongly predisposes to bacterial keratitis.
Diagnosis
History
Subconjunctival hemorrhage is unilateral, painless, and vision is unaffected. Conjunctivitis often begins in one eye but is commonly bilateral and features discharge with minimal visual change. Keratitis is usually unilateral and associated with redness, foreign body sensation, tearing, and decreased vision. Uveitis presents with reduced vision, photophobia, and ocular pain. Acute angle-closure glaucoma presents with severe unilateral pain, decreased vision, nausea, and vomiting. Anterior scleritis causes severe pain and tenderness; posterior scleritis may cause significant visual impairment with less obvious redness. Episcleritis resembles conjunctivitis but has mild discomfort and no discharge. Endophthalmitis presents with pain and significant vision loss.
Physical Examination
Slit-lamp examination is essential. Subconjunctival hemorrhage appears as a sharply demarcated red patch under the conjunctiva. Conjunctivitis shows hyperemia, discharge, membranes or pseudomembranes, papillary or follicular reaction, and possibly preauricular lymphadenopathy. Keratitis reveals epithelial defects, stromal opacities, discharge, and anterior chamber inflammation. Anterior uveitis is diagnosed by inflammatory cells in the anterior chamber and keratic precipitates. Acute angle closure presents with a mid-dilated poorly reactive pupil, corneal edema, and elevated intraocular pressure.
Diagnostic Tests and Interpretation
Laboratory Studies
Routine cultures are unnecessary in typical conjunctivitis except in hyperacute cases suggestive of Neisseria gonorrhoeae. Keratitis lesions are sampled for Gram stain and culture.
Imaging
Confocal microscopy assists in diagnosing Acanthamoeba keratitis. Neuroimaging may identify vascular abnormalities such as carotid-cavernous fistulas or arteriovenous malformations associated with red eye.
Diagnostic Procedures/Other
Corneal biopsy may be needed for refractory keratitis. Vitreous sampling during vitrectomy can assist in diagnosing uveitis or endophthalmitis via cytology, culture, and PCR.
Differential Diagnosis
Key distinguishing features include:
Visual acuity is typically preserved in conjunctivitis and subconjunctival hemorrhage but reduced in uveitis, keratitis, and acute angle closure. Discharge is common in conjunctivitis and keratitis but absent in subconjunctival hemorrhage, uveitis, and acute angle closure. Pain is absent in conjunctivitis and subconjunctival hemorrhage but present in uveitis, keratitis, and acute angle closure. Photophobia is typical of uveitis and sometimes keratitis. Pruritus suggests allergic conjunctivitis.
Treatment
Medications
Viral conjunctivitis is managed supportively with artificial tears and cold compresses; topical steroids are rarely required. Mild bacterial conjunctivitis is treated with topical antibiotics such as trimethoprim-polymyxin B or a fluoroquinolone for several days. Bacterial keratitis requires intensive fortified topical antibiotics administered hourly. Acute bacterial endophthalmitis is treated with intravitreal antibiotics targeting gram-positive and gram-negative organisms. Anterior uveitis is treated with topical corticosteroids and cycloplegic agents; infectious causes require specific antimicrobial therapy. Acute angle-closure glaucoma requires urgent reduction of intraocular pressure with systemic acetazolamide, intravenous mannitol, topical beta-blockers, and pilocarpine, followed by laser iridotomy. Episcleritis is treated with artificial tears, topical steroids, and oral NSAIDs. Scleritis often requires systemic corticosteroids and may necessitate immunomodulatory therapy depending on associated systemic disease.
Additional Treatment / Surgery
Laser iridotomy is definitive for angle closure after stabilization. Severe infectious keratitis or scleritis causing tissue thinning may require surgical grafting.
Prognosis
Outcome depends on etiology, ranging from benign in subconjunctival hemorrhage to guarded in endophthalmitis.
Complications
Chronic inflammation may lead to cataract formation, secondary glaucoma, and cystoid macular edema.
Basics
Description
Red eye may result from sight-threatening conditions such as uveitis, endophthalmitis, acute angle-closure glaucoma, or scleritis, which typically produce ciliary injection. More commonly, redness is due to conjunctival hyperemia associated with conjunctivitis, keratitis, dry eye disease, foreign body irritation (including contact lenses), blepharitis, or environmental irritants. Ocular trauma may cause subconjunctival hemorrhage. Not all causes are infectious. Uveitis involves intraocular inflammation and may be anterior, posterior, or pan-uveitis. Endophthalmitis is a severe intraocular infection involving the vitreous cavity. Acute angle-closure glaucoma is an ophthalmic emergency caused by obstruction of aqueous outflow and elevated intraocular pressure. Episcleritis affects superficial scleral tissues, while scleritis is a deeper, more severe inflammatory process that may occur with keratitis or uveitis. Conjunctivitis is the most common cause of red eye and usually includes discharge. Keratitis primarily affects the cornea.
Epidemiology
Primary acute angle closure occurs more frequently in Asian populations than in Caucasians. Incidence rates for conjunctivitis, keratitis, and uveitis vary and are addressed in their respective discussions.
Risk Factors
Risk factors for angle-closure glaucoma include advanced age, hyperopia, cataract, female sex, prior angle closure in the fellow eye, and Asian ethnicity; prophylactic laser iridotomy is often performed in the unaffected eye. Contact lens use increases the risk of bacterial keratitis. Subconjunctival hemorrhage may occur spontaneously or with bleeding disorders, minor trauma, or increased venous pressure from coughing or sneezing. Autoimmune connective tissue disorders are associated with ocular inflammation, and uveitis may be an initial manifestation.
General Prevention
Proper contact lens hygiene reduces infectious and inflammatory complications. Screening with gonioscopy and preventive laser iridotomy can prevent acute angle closure in high-risk individuals.
Pathophysiology
Ciliary injection involves deeper vascular branches and indicates inflammation of the cornea, iris, ciliary body, or sclera. Conjunctival injection is superficial, mobile with the conjunctiva, and improves with topical vasoconstrictors. Acute angle closure usually results from pupillary block, causing pressure differential between the posterior and anterior chambers, forward bowing of the iris, and obstruction of aqueous outflow through the trabecular meshwork.
Etiology
Conjunctivitis, keratitis, uveitis, and endophthalmitis have infectious and noninfectious causes. Acute angle-closure glaucoma and subconjunctival hemorrhage are noninfectious. Episcleritis is usually idiopathic, though immunologic reactions to herpes simplex or varicella zoster may occur. Scleritis is rarely infectious but may result from systemic infections or extension from keratitis; reported pathogens include fungi (Aspergillus, Fusarium), herpes viruses, mycobacteria, Nocardia, Pseudomonas, Proteus (after scleral buckle procedures), syphilis, leprosy, Lyme disease, and tuberculosis.
Commonly Associated Conditions
Endophthalmitis most commonly follows intraocular surgery. Contact lens wear strongly predisposes to bacterial keratitis.
Diagnosis
History
Subconjunctival hemorrhage is unilateral, painless, and vision is unaffected. Conjunctivitis often begins in one eye but is commonly bilateral and features discharge with minimal visual change. Keratitis is usually unilateral and associated with redness, foreign body sensation, tearing, and decreased vision. Uveitis presents with reduced vision, photophobia, and ocular pain. Acute angle-closure glaucoma presents with severe unilateral pain, decreased vision, nausea, and vomiting. Anterior scleritis causes severe pain and tenderness; posterior scleritis may cause significant visual impairment with less obvious redness. Episcleritis resembles conjunctivitis but has mild discomfort and no discharge. Endophthalmitis presents with pain and significant vision loss.
Physical Examination
Slit-lamp examination is essential. Subconjunctival hemorrhage appears as a sharply demarcated red patch under the conjunctiva. Conjunctivitis shows hyperemia, discharge, membranes or pseudomembranes, papillary or follicular reaction, and possibly preauricular lymphadenopathy. Keratitis reveals epithelial defects, stromal opacities, discharge, and anterior chamber inflammation. Anterior uveitis is diagnosed by inflammatory cells in the anterior chamber and keratic precipitates. Acute angle closure presents with a mid-dilated poorly reactive pupil, corneal edema, and elevated intraocular pressure.
Diagnostic Tests and Interpretation
Laboratory Studies
Routine cultures are unnecessary in typical conjunctivitis except in hyperacute cases suggestive of Neisseria gonorrhoeae. Keratitis lesions are sampled for Gram stain and culture.
Imaging
Confocal microscopy assists in diagnosing Acanthamoeba keratitis. Neuroimaging may identify vascular abnormalities such as carotid-cavernous fistulas or arteriovenous malformations associated with red eye.
Diagnostic Procedures/Other
Corneal biopsy may be needed for refractory keratitis. Vitreous sampling during vitrectomy can assist in diagnosing uveitis or endophthalmitis via cytology, culture, and PCR.
Differential Diagnosis
Key distinguishing features include:
Visual acuity is typically preserved in conjunctivitis and subconjunctival hemorrhage but reduced in uveitis, keratitis, and acute angle closure. Discharge is common in conjunctivitis and keratitis but absent in subconjunctival hemorrhage, uveitis, and acute angle closure. Pain is absent in conjunctivitis and subconjunctival hemorrhage but present in uveitis, keratitis, and acute angle closure. Photophobia is typical of uveitis and sometimes keratitis. Pruritus suggests allergic conjunctivitis.
Treatment
Medications
Viral conjunctivitis is managed supportively with artificial tears and cold compresses; topical steroids are rarely required. Mild bacterial conjunctivitis is treated with topical antibiotics such as trimethoprim-polymyxin B or a fluoroquinolone for several days. Bacterial keratitis requires intensive fortified topical antibiotics administered hourly. Acute bacterial endophthalmitis is treated with intravitreal antibiotics targeting gram-positive and gram-negative organisms. Anterior uveitis is treated with topical corticosteroids and cycloplegic agents; infectious causes require specific antimicrobial therapy. Acute angle-closure glaucoma requires urgent reduction of intraocular pressure with systemic acetazolamide, intravenous mannitol, topical beta-blockers, and pilocarpine, followed by laser iridotomy. Episcleritis is treated with artificial tears, topical steroids, and oral NSAIDs. Scleritis often requires systemic corticosteroids and may necessitate immunomodulatory therapy depending on associated systemic disease.
Additional Treatment / Surgery
Laser iridotomy is definitive for angle closure after stabilization. Severe infectious keratitis or scleritis causing tissue thinning may require surgical grafting.
Prognosis
Outcome depends on etiology, ranging from benign in subconjunctival hemorrhage to guarded in endophthalmitis.
Complications
Chronic inflammation may lead to cataract formation, secondary glaucoma, and cystoid macular edema.
- Published on
Infectious Diseases and Microbiology: Rash and Fever
Basics
Description
Rash refers to temporary skin eruptions that accompany localized or generalized infectious diseases. This topic emphasizes the differential diagnosis and early recognition of potentially life-threatening generalized eruptions.
Approach to the Patient
A detailed history should assess immune status, full medication list, travel history, immunization record, exposure to pets or animals, arthropod bites, cardiac abnormalities, prosthetic material, recent contact with ill persons, and possible sexually transmitted infections. Clarify the initial site of rash, pruritus or pain, and speed and direction of spread. Document associated symptoms including prodrome, fever, and itching. Physical examination should define lesion morphology (macules, papules, vesicles, plaques, nodules), configuration (annular, target), arrangement, and distribution (central versus peripheral).
Epidemiology
Infectious mononucleosis may present with generalized maculopapular, petechial, or urticarial rash, often after antibiotic exposure. Approximately one-fifth of erythema infectiosum cases occur in adults, though rash may resemble rubella. Up to half of patients with primary HIV infection develop a maculopapular rash within days of fever onset, typically involving the upper trunk and face. Rubella has been declared eliminated in the United States. Cutaneous leishmaniasis affects up to 1.5 million individuals annually worldwide. Rash occurs in about half of dengue cases. In early Lyme disease, erythema migrans develops at the tick bite site in most patients.
General Prevention
Women of reproductive age should be immunized against rubella. Pregnant women diagnosed with early rubella infection should receive counseling regarding fetal risks and management options.
Etiology
Common adult rash patterns include centrally distributed maculopapular eruptions (such as dengue, infectious mononucleosis, leptospirosis, Lyme disease, primary HIV infection, rubella, measles, typhoid fever, systemic lupus erythematosus, and various rickettsial infections), peripheral eruptions (including bacterial endocarditis, chronic meningococcemia, disseminated gonococcal infection, erythema multiforme, Rocky Mountain spotted fever, and secondary syphilis), confluent desquamative erythemas (graft-versus-host disease, Kawasaki disease, scarlet fever, staphylococcal and streptococcal toxic shock syndromes), vesiculobullous eruptions (disseminated Vibrio vulnificus infection, ecthyma gangrenosum, rickettsialpox), nodular eruptions (disseminated fungal or mycobacterial infections, erythema nodosum, Sweet syndrome), and purpuric eruptions (acute or chronic meningococcemia, disseminated gonococcal infection, enteroviral petechiae, Rocky Mountain spotted fever, thrombotic thrombocytopenic purpura).
Diagnosis
Rocky Mountain spotted fever (RMSF) typically presents with rash around day four of illness, beginning as blanching macules that may progress to purpura and necrosis; genital involvement may be suggestive. Rash may be absent in some cases and is associated with worse prognosis. Meningococcal disease often produces petechiae that evolve into palpable purpura, though other lesion types can occur. Fulminant meningococcemia with disseminated intravascular coagulation constitutes Waterhouse–Friderichsen syndrome. Cutaneous findings in infective endocarditis include vascular phenomena such as petechiae, splinter hemorrhages, and Janeway lesions, and immunologic signs such as Osler nodes and Roth spots. Lyme disease progresses from erythema migrans to neurologic or cardiac involvement and later arthritis or chronic skin changes. Ehrlichiosis often features headache and high fever, with variable rash. Staphylococcal toxic shock syndrome presents with diffuse erythematous rash resembling sunburn, followed by desquamation within two weeks, along with conjunctival injection, mucosal hyperemia, and strawberry tongue. Streptococcal toxic shock syndrome often arises from invasive soft-tissue infection. Dengue rash is typically maculopapular and appears within several days of illness onset.
Diagnostic Tests and Interpretation
Laboratory Studies
Gram stain and culture of pustular or bullous lesions should be performed when infection is suspected. Antibodies to Rickettsia rickettsii become detectable after the first week of RMSF. Meningococcal disease is confirmed by Gram stain and culture of blood or cerebrospinal fluid; skin biopsy may assist. Streptococcal toxic shock syndrome more commonly involves bacteremia than staphylococcal toxic shock syndrome.
Diagnostic Procedures/Other
Skin biopsy with culture and histopathologic examination may establish diagnosis in unclear cases.
Differential Diagnosis
Desquamating erythroderma is more common in staphylococcal than streptococcal toxic shock syndrome. Gonococcemia frequently causes a pustular hemorrhagic rash but may present with diverse lesion types.
Treatment
Management depends on the underlying etiology and may require urgent antimicrobial or supportive therapy.
Ongoing Care and Follow-Up
Serial documentation of rash progression with photography or ink demarcation can assist monitoring.
Complications
Untreated Rocky Mountain spotted fever carries high mortality, underscoring the importance of early recognition and treatment.
I’
Basics
Description
Rash refers to temporary skin eruptions that accompany localized or generalized infectious diseases. This topic emphasizes the differential diagnosis and early recognition of potentially life-threatening generalized eruptions.
Approach to the Patient
A detailed history should assess immune status, full medication list, travel history, immunization record, exposure to pets or animals, arthropod bites, cardiac abnormalities, prosthetic material, recent contact with ill persons, and possible sexually transmitted infections. Clarify the initial site of rash, pruritus or pain, and speed and direction of spread. Document associated symptoms including prodrome, fever, and itching. Physical examination should define lesion morphology (macules, papules, vesicles, plaques, nodules), configuration (annular, target), arrangement, and distribution (central versus peripheral).
Epidemiology
Infectious mononucleosis may present with generalized maculopapular, petechial, or urticarial rash, often after antibiotic exposure. Approximately one-fifth of erythema infectiosum cases occur in adults, though rash may resemble rubella. Up to half of patients with primary HIV infection develop a maculopapular rash within days of fever onset, typically involving the upper trunk and face. Rubella has been declared eliminated in the United States. Cutaneous leishmaniasis affects up to 1.5 million individuals annually worldwide. Rash occurs in about half of dengue cases. In early Lyme disease, erythema migrans develops at the tick bite site in most patients.
General Prevention
Women of reproductive age should be immunized against rubella. Pregnant women diagnosed with early rubella infection should receive counseling regarding fetal risks and management options.
Etiology
Common adult rash patterns include centrally distributed maculopapular eruptions (such as dengue, infectious mononucleosis, leptospirosis, Lyme disease, primary HIV infection, rubella, measles, typhoid fever, systemic lupus erythematosus, and various rickettsial infections), peripheral eruptions (including bacterial endocarditis, chronic meningococcemia, disseminated gonococcal infection, erythema multiforme, Rocky Mountain spotted fever, and secondary syphilis), confluent desquamative erythemas (graft-versus-host disease, Kawasaki disease, scarlet fever, staphylococcal and streptococcal toxic shock syndromes), vesiculobullous eruptions (disseminated Vibrio vulnificus infection, ecthyma gangrenosum, rickettsialpox), nodular eruptions (disseminated fungal or mycobacterial infections, erythema nodosum, Sweet syndrome), and purpuric eruptions (acute or chronic meningococcemia, disseminated gonococcal infection, enteroviral petechiae, Rocky Mountain spotted fever, thrombotic thrombocytopenic purpura).
Diagnosis
Rocky Mountain spotted fever (RMSF) typically presents with rash around day four of illness, beginning as blanching macules that may progress to purpura and necrosis; genital involvement may be suggestive. Rash may be absent in some cases and is associated with worse prognosis. Meningococcal disease often produces petechiae that evolve into palpable purpura, though other lesion types can occur. Fulminant meningococcemia with disseminated intravascular coagulation constitutes Waterhouse–Friderichsen syndrome. Cutaneous findings in infective endocarditis include vascular phenomena such as petechiae, splinter hemorrhages, and Janeway lesions, and immunologic signs such as Osler nodes and Roth spots. Lyme disease progresses from erythema migrans to neurologic or cardiac involvement and later arthritis or chronic skin changes. Ehrlichiosis often features headache and high fever, with variable rash. Staphylococcal toxic shock syndrome presents with diffuse erythematous rash resembling sunburn, followed by desquamation within two weeks, along with conjunctival injection, mucosal hyperemia, and strawberry tongue. Streptococcal toxic shock syndrome often arises from invasive soft-tissue infection. Dengue rash is typically maculopapular and appears within several days of illness onset.
Diagnostic Tests and Interpretation
Laboratory Studies
Gram stain and culture of pustular or bullous lesions should be performed when infection is suspected. Antibodies to Rickettsia rickettsii become detectable after the first week of RMSF. Meningococcal disease is confirmed by Gram stain and culture of blood or cerebrospinal fluid; skin biopsy may assist. Streptococcal toxic shock syndrome more commonly involves bacteremia than staphylococcal toxic shock syndrome.
Diagnostic Procedures/Other
Skin biopsy with culture and histopathologic examination may establish diagnosis in unclear cases.
Differential Diagnosis
Desquamating erythroderma is more common in staphylococcal than streptococcal toxic shock syndrome. Gonococcemia frequently causes a pustular hemorrhagic rash but may present with diverse lesion types.
Treatment
Management depends on the underlying etiology and may require urgent antimicrobial or supportive therapy.
Ongoing Care and Follow-Up
Serial documentation of rash progression with photography or ink demarcation can assist monitoring.
Complications
Untreated Rocky Mountain spotted fever carries high mortality, underscoring the importance of early recognition and treatment.
I’
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Infectious Diseases and Microbiology: Postoperative Fever
Basics
Description
Postoperative fever is defined as a body temperature above 38°C (100.4°F) occurring after an invasive procedure. It is classified by timing: immediate (during surgery or within hours), acute (within the first postoperative week), subacute (1–4 weeks after surgery), and delayed (more than one month postoperatively). Most cases result from the inflammatory response to surgery and resolve spontaneously, but fever may signal a serious complication. Evaluation requires careful history, physical examination, and appropriate laboratory and imaging studies, including cultures and Gram stains when indicated. Early postoperative fever is frequently noninfectious; however, fever persisting beyond 96 hours is more likely infectious. Consider that patients may have been incubating community-acquired infection preoperatively. New or persistent fever beyond four days strongly suggests ongoing pathology or a new complication. Surgical wounds, catheter insertion sites, and all dressings must be inspected, and recent interventions such as blood transfusions reviewed.
Epidemiology
Drug fever is the most common noninfectious cause of postoperative fever, most often linked to antimicrobials and heparin. Pneumonia is a common cause after cardiac surgery and occurs in more than 5% of such patients. Sternal wound infections after cardiothoracic surgery occur in up to 5%, typically around postoperative day seven. Postoperative aspergillosis after cardiothoracic procedures carries very high mortality. Fever alone is a poor predictor of infection, with low sensitivity. Postsurgical mediastinitis has high mortality. In obstetrics and gynecology, bacterial vaginosis may increase postoperative infection risk.
General Prevention
Aggressive pulmonary hygiene, including incentive spirometry and mobilization, reduces pulmonary complications such as atelectasis.
Etiology
Common infectious causes include urinary tract infection, pneumonia, sinusitis, suppurative thrombophlebitis, catheter-related infections, and Clostridioides difficile–associated diarrhea. Noninfectious causes include deep venous thrombosis, pulmonary embolism, subarachnoid hemorrhage, gout, and fat embolism. Surgical site infections are uncommon within the first 1–3 days except for aggressive pathogens such as group A streptococci or clostridia, which can present early. Atelectasis is frequently blamed but likely coincidental rather than causal. Other serious causes include transplant rejection. Drug-induced fever is most often associated with beta-lactams, antiepileptics, and heparin. Inflammatory states such as acute myocardial infarction, pancreatitis, or acute respiratory distress syndrome may produce fever without infection. Endocrine emergencies such as adrenal insufficiency or thyrotoxicosis may also present with fever.
Diagnosis
Physical Examination
Drug fever lacks specific features and usually develops days after medication exposure; rash and eosinophilia are uncommon. Malignant hyperthermia typically occurs intraoperatively but may be delayed up to 24 hours and is associated with agents such as succinylcholine or volatile anesthetics. Neuroleptic malignant syndrome is associated with antipsychotics, particularly haloperidol. Withdrawal syndromes from alcohol, opioids, barbiturates, or benzodiazepines may cause fever hours to days after admission, and prior substance use history may not be readily available.
Diagnostic Tests and Interpretation
Laboratory Studies
Urinalysis and urine culture are recommended in patients with indwelling catheters longer than 72 hours. Procalcitonin has uncertain value in distinguishing bacterial causes of postoperative fever.
Imaging
Duplex ultrasonography with Doppler should be considered for new extremity swelling suggestive of deep venous thrombosis. Routine chest radiography is not required within the first 72 postoperative hours if fever is the only indication.
Diagnostic Procedures/Other
Wound swab cultures are rarely useful unless there is clear clinical evidence of infection. Suspected deep intraabdominal abscess may require imaging and, if inconclusive, surgical exploration.
Treatment
Medications
Antibiotics are generally not indicated for early postoperative fever without evidence of infection. Critically ill patients or those with hemodynamic instability should receive empiric broad-spectrum antibiotics after thorough evaluation, but therapy should be discontinued after 48 hours if no infectious source is identified. Atelectasis management includes coughing exercises, incentive spirometry, chest physiotherapy, beta-2 agonists, intermittent positive-pressure breathing, and nebulization. Empiric antifungal therapy is not recommended initially.
Ongoing Care and Follow-Up
Drug fever is diagnosed by exclusion when other causes are ruled out. Surgical wounds and invasive device sites must be repeatedly examined for signs of infection.
Complications
Postoperative infections increase morbidity and mortality, may lead to sepsis, impair wound healing, and cause respiratory failure and other serious outcomes.
Basics
Description
Postoperative fever is defined as a body temperature above 38°C (100.4°F) occurring after an invasive procedure. It is classified by timing: immediate (during surgery or within hours), acute (within the first postoperative week), subacute (1–4 weeks after surgery), and delayed (more than one month postoperatively). Most cases result from the inflammatory response to surgery and resolve spontaneously, but fever may signal a serious complication. Evaluation requires careful history, physical examination, and appropriate laboratory and imaging studies, including cultures and Gram stains when indicated. Early postoperative fever is frequently noninfectious; however, fever persisting beyond 96 hours is more likely infectious. Consider that patients may have been incubating community-acquired infection preoperatively. New or persistent fever beyond four days strongly suggests ongoing pathology or a new complication. Surgical wounds, catheter insertion sites, and all dressings must be inspected, and recent interventions such as blood transfusions reviewed.
Epidemiology
Drug fever is the most common noninfectious cause of postoperative fever, most often linked to antimicrobials and heparin. Pneumonia is a common cause after cardiac surgery and occurs in more than 5% of such patients. Sternal wound infections after cardiothoracic surgery occur in up to 5%, typically around postoperative day seven. Postoperative aspergillosis after cardiothoracic procedures carries very high mortality. Fever alone is a poor predictor of infection, with low sensitivity. Postsurgical mediastinitis has high mortality. In obstetrics and gynecology, bacterial vaginosis may increase postoperative infection risk.
General Prevention
Aggressive pulmonary hygiene, including incentive spirometry and mobilization, reduces pulmonary complications such as atelectasis.
Etiology
Common infectious causes include urinary tract infection, pneumonia, sinusitis, suppurative thrombophlebitis, catheter-related infections, and Clostridioides difficile–associated diarrhea. Noninfectious causes include deep venous thrombosis, pulmonary embolism, subarachnoid hemorrhage, gout, and fat embolism. Surgical site infections are uncommon within the first 1–3 days except for aggressive pathogens such as group A streptococci or clostridia, which can present early. Atelectasis is frequently blamed but likely coincidental rather than causal. Other serious causes include transplant rejection. Drug-induced fever is most often associated with beta-lactams, antiepileptics, and heparin. Inflammatory states such as acute myocardial infarction, pancreatitis, or acute respiratory distress syndrome may produce fever without infection. Endocrine emergencies such as adrenal insufficiency or thyrotoxicosis may also present with fever.
Diagnosis
Physical Examination
Drug fever lacks specific features and usually develops days after medication exposure; rash and eosinophilia are uncommon. Malignant hyperthermia typically occurs intraoperatively but may be delayed up to 24 hours and is associated with agents such as succinylcholine or volatile anesthetics. Neuroleptic malignant syndrome is associated with antipsychotics, particularly haloperidol. Withdrawal syndromes from alcohol, opioids, barbiturates, or benzodiazepines may cause fever hours to days after admission, and prior substance use history may not be readily available.
Diagnostic Tests and Interpretation
Laboratory Studies
Urinalysis and urine culture are recommended in patients with indwelling catheters longer than 72 hours. Procalcitonin has uncertain value in distinguishing bacterial causes of postoperative fever.
Imaging
Duplex ultrasonography with Doppler should be considered for new extremity swelling suggestive of deep venous thrombosis. Routine chest radiography is not required within the first 72 postoperative hours if fever is the only indication.
Diagnostic Procedures/Other
Wound swab cultures are rarely useful unless there is clear clinical evidence of infection. Suspected deep intraabdominal abscess may require imaging and, if inconclusive, surgical exploration.
Treatment
Medications
Antibiotics are generally not indicated for early postoperative fever without evidence of infection. Critically ill patients or those with hemodynamic instability should receive empiric broad-spectrum antibiotics after thorough evaluation, but therapy should be discontinued after 48 hours if no infectious source is identified. Atelectasis management includes coughing exercises, incentive spirometry, chest physiotherapy, beta-2 agonists, intermittent positive-pressure breathing, and nebulization. Empiric antifungal therapy is not recommended initially.
Ongoing Care and Follow-Up
Drug fever is diagnosed by exclusion when other causes are ruled out. Surgical wounds and invasive device sites must be repeatedly examined for signs of infection.
Complications
Postoperative infections increase morbidity and mortality, may lead to sepsis, impair wound healing, and cause respiratory failure and other serious outcomes.
- Published on
Infectious Diseases and Microbiology: Genital Lesions and Ulcers
Basics
Description
Genital lesions involve the reproductive organs and can result from a range of infectious and noninfectious conditions.
Epidemiology
Genital ulcers are the most frequent sexually transmitted cause of genital lesions. In North America and Europe, the leading sexually transmitted causes of genital ulcer disease are herpes simplex and syphilis. In the United States, a substantial proportion of people aged 14–49 have HSV-2 infection, and HSV-1 accounts for a significant minority of genital herpes cases. Chancroid is more common in Africa, Asia, and Latin America but can occur in sporadic U.S. outbreaks. Lymphogranuloma venereum is uncommon in industrialized countries, though outbreaks have been reported among men who have sex with men.
Risk Factors
About half of exposed sexual partners may acquire genital warts (HPV) after contact with an infected partner. Sexual transmission of syphilis can be high, with rates reported up to roughly one-third per exposure.
General Prevention
Risk reduction includes abstinence, consistent condom use, limiting partners, safer-sex practices, and HPV vaccination. Two HPV vaccines are available for females aged 9–26 that protect against HPV 6 and 11 (responsible for most genital warts) and HPV 16 and 18 (responsible for a large proportion of cervical cancers): the quadrivalent vaccine (Gardasil) and the bivalent vaccine (Cervarix). Quadrivalent vaccination in males aged 9–26 can reduce genital warts.
Etiology
Infectious Ulcers
Common causes include genital herpes, syphilis due to Treponema pallidum, chancroid due to Haemophilus ducreyi, lymphogranuloma venereum from Chlamydia trachomatis serovars L1–L3, donovanosis (granuloma inguinale) from Klebsiella granulomatis, and less commonly tuberculosis or tularemia. Additional reported etiologies include candidiasis, histoplasmosis, amebiasis, gonorrhea, and trichomoniasis. Acute or primary HIV infection can present with genital ulcers, and a notable minority of ulcer cases involve more than one pathogen.
Noninfectious Ulcers
Noninfectious causes include trauma, fixed drug eruption, malignancy, systemic lupus erythematosus, and Behçet disease.
Other Lesion Patterns
Papules may be due to candidiasis, molluscum contagiosum, scabies, syphilis, or condylomata acuminata from HPV, with types 6 and 11 most common and types 16, 18, 31, 33, and 35 linked to cervical dysplasia. Vesicles or bullae suggest herpes, impetigo, or scabies. Diffuse erythema may occur with candidiasis, erysipelas often after trauma or surgery, contact dermatitis, drug eruption, psoriasis, or trauma. Other patterns include benign cysts, nodules from hidradenitis or furunculosis, and crusted lesions from herpes or scabies
.
Commonly Associated Conditions
HIV and other sexually transmitted infections commonly coexist with genital lesions.
Diagnosis
History
Key points include time of onset, associated symptoms, immunodeficiency, prior sexually transmitted infections, prior similar lesions, and travel. Typical incubation periods vary by cause, including herpes within days but sometimes up to weeks, genital warts usually weeks to months, syphilis typically weeks but up to months, chancroid usually within a week but variable, donovanosis over weeks, molluscum potentially months, and ectoparasites such as pubic lice or scabies often after several weeks. Lesions appearing within hours of exposure suggest trauma, chemical irritation, or hypersensitivity. Itching is common early in herpes and with scabies or pubic lice, and mild pruritus can occur in secondary syphilis.
Physical Examination
Define lesion morphology and distribution, determine whether disease is localized or generalized, assess tenderness, lymphadenopathy, and any urethral or vaginal discharge, and examine buccal mucosa and perianal skin; pelvic examination or prostate assessment is often needed. Early herpes often begins as clustered vesicles on an erythematous base, may show umbilication, is typically very painful, and is often ulcerated by presentation. Pain is typical of herpes, chancroid, and tularemia, whereas donovanosis ulcers are usually painless. Ulcer base and borders can help narrow the differential: Behçet ulcers may be yellow and necrotic, chancroid bases are often necrotic, donovanosis can appear beefy red with hypertrophy, and syphilitic and herpetic ulcers may have cleaner bases; chancroid ulcers are classically nonindurated with irregular erythematous edges, syphilitic ulcers are indurated, and herpetic ulcers often have erythematous borders. Primary syphilis more often produces a solitary lesion, while chancroid often causes multiple ulcers of varying size. Behçet disease can cause recurrent, multiple genital ulcers involving scrotum or vulva and may be accompanied by recurrent oral ulcers and skin or eye disease, which may not occur simultaneously. Linear burrows suggest scabies, and reddish specks may reflect crab louse excreta. Urethral discharge suggests gonorrhea or reactive arthritis. In adults with genital lesions, inguinal lymphadenopathy supports consideration of chancroid, LGV, syphilis, herpes, lymphoma, or tuberculosis. LGV ulcers may be unnoticed and heal spontaneously, followed weeks later by painful inguinal lymphadenopathy and systemic symptoms, and untreated disease can progress to elephantiasis-like genital distortion. Lymphadenopathy tends to be unilateral in chancroid and LGV and more often bilateral in genital herpes. Painful perianal ulcers or mucosal ulcers seen on anoscopy should be treated presumptively for HSV and LGV. Molluscum contagiosum causes mildly contagious umbilicated papules up to about 1 cm, and advanced HIV may cause widespread or large lesions. Tuberculous genital lesions may appear as chronic minimally painful red, firm, nodular sores. Clinical appearance alone is often insufficient for diagnosis.
Diagnostic Tests and Interpretation
Laboratory Studies
All patients with genital, anal, or perianal ulcers should receive syphilis serology with dark-field examination when available, HSV testing by culture or PCR or type-specific serology, and HIV testing. If suspicion and culture capacity exist, obtain H. ducreyi culture for chancroid. Donovanosis can be supported by identifying intracellular Donovan bodies on Giemsa or Wright stain from lesion scrapings or biopsy, with biopsy favored when malignancy is possible. Chancroid culture can be sensitive but is limited by availability of selective media; a probable diagnosis relies on painful ulcers typical of chancroid with negative testing for syphilis and HSV. LGV diagnosis is supported by serology or by isolating C. trachomatis with confirmation of L1–L3 serovars. Molluscum can be confirmed by histology and electron microscopy. Chancres may be missed by patients, and early syphilis serology can be falsely negative; when diagnosis is uncertain or cancer is possible, biopsy is indicated.
Treatment
Medications
Chancroid can be treated with single-dose azithromycin 1 g orally or ceftriaxone 250 mg intramuscularly. Condylomata acuminata have no single best therapy; options include imiquimod 5% cream three times weekly for up to 16 weeks or podofilox 0.5% solution or gel twice daily for three days followed by one day off, repeated in cycles. Donovanosis can be treated for more than three weeks with trimethoprim-sulfamethoxazole, tetracycline, or doxycycline. Genital herpes is treated with acyclovir, famciclovir, or valacyclovir for 7–10 days, with intravenous acyclovir for severe disease. Tuberculous genital lesions require systemic antituberculosis therapy. LGV is treated with doxycycline 100 mg twice daily for 21 days. Molluscum contagiosum can be managed with lesion destruction via desiccation, cryotherapy, or curettage.
Complementary and Alternative Therapies
Alternative chancroid regimens include erythromycin for seven days or ciprofloxacin for three days. Wart management can include cryosurgery, excision, electrosurgery, or laser therapy. Donovanosis alternatives include prolonged ciprofloxacin, erythromycin, or chloramphenicol. LGV can also be treated with erythromycin four times daily for 21 days.
Ongoing Care and Follow-Up
Patients should be encouraged to have sexual partners evaluated and treated. HIV testing should be performed at diagnosis and repeated with syphilis serology about three months later if initially negative. Consider cervical cytology screening for patients evaluated for sexually transmitted infections who have not had a Pap smear within the past year, and counsel patients with HPV on the need for ongoing screening.
Pediatric Considerations
Sexually transmitted genital lesions in a child require evaluation for sexual abuse.
Complications
Untreated primary syphilis can disseminate and progress to secondary disease within weeks. Chancroid, genital herpes, and syphilis increase susceptibility to HIV transmission.
Basics
Description
Genital lesions involve the reproductive organs and can result from a range of infectious and noninfectious conditions.
Epidemiology
Genital ulcers are the most frequent sexually transmitted cause of genital lesions. In North America and Europe, the leading sexually transmitted causes of genital ulcer disease are herpes simplex and syphilis. In the United States, a substantial proportion of people aged 14–49 have HSV-2 infection, and HSV-1 accounts for a significant minority of genital herpes cases. Chancroid is more common in Africa, Asia, and Latin America but can occur in sporadic U.S. outbreaks. Lymphogranuloma venereum is uncommon in industrialized countries, though outbreaks have been reported among men who have sex with men.
Risk Factors
About half of exposed sexual partners may acquire genital warts (HPV) after contact with an infected partner. Sexual transmission of syphilis can be high, with rates reported up to roughly one-third per exposure.
General Prevention
Risk reduction includes abstinence, consistent condom use, limiting partners, safer-sex practices, and HPV vaccination. Two HPV vaccines are available for females aged 9–26 that protect against HPV 6 and 11 (responsible for most genital warts) and HPV 16 and 18 (responsible for a large proportion of cervical cancers): the quadrivalent vaccine (Gardasil) and the bivalent vaccine (Cervarix). Quadrivalent vaccination in males aged 9–26 can reduce genital warts.
Etiology
Infectious Ulcers
Common causes include genital herpes, syphilis due to Treponema pallidum, chancroid due to Haemophilus ducreyi, lymphogranuloma venereum from Chlamydia trachomatis serovars L1–L3, donovanosis (granuloma inguinale) from Klebsiella granulomatis, and less commonly tuberculosis or tularemia. Additional reported etiologies include candidiasis, histoplasmosis, amebiasis, gonorrhea, and trichomoniasis. Acute or primary HIV infection can present with genital ulcers, and a notable minority of ulcer cases involve more than one pathogen.
Noninfectious Ulcers
Noninfectious causes include trauma, fixed drug eruption, malignancy, systemic lupus erythematosus, and Behçet disease.
Other Lesion Patterns
Papules may be due to candidiasis, molluscum contagiosum, scabies, syphilis, or condylomata acuminata from HPV, with types 6 and 11 most common and types 16, 18, 31, 33, and 35 linked to cervical dysplasia. Vesicles or bullae suggest herpes, impetigo, or scabies. Diffuse erythema may occur with candidiasis, erysipelas often after trauma or surgery, contact dermatitis, drug eruption, psoriasis, or trauma. Other patterns include benign cysts, nodules from hidradenitis or furunculosis, and crusted lesions from herpes or scabies
.
Commonly Associated Conditions
HIV and other sexually transmitted infections commonly coexist with genital lesions.
Diagnosis
History
Key points include time of onset, associated symptoms, immunodeficiency, prior sexually transmitted infections, prior similar lesions, and travel. Typical incubation periods vary by cause, including herpes within days but sometimes up to weeks, genital warts usually weeks to months, syphilis typically weeks but up to months, chancroid usually within a week but variable, donovanosis over weeks, molluscum potentially months, and ectoparasites such as pubic lice or scabies often after several weeks. Lesions appearing within hours of exposure suggest trauma, chemical irritation, or hypersensitivity. Itching is common early in herpes and with scabies or pubic lice, and mild pruritus can occur in secondary syphilis.
Physical Examination
Define lesion morphology and distribution, determine whether disease is localized or generalized, assess tenderness, lymphadenopathy, and any urethral or vaginal discharge, and examine buccal mucosa and perianal skin; pelvic examination or prostate assessment is often needed. Early herpes often begins as clustered vesicles on an erythematous base, may show umbilication, is typically very painful, and is often ulcerated by presentation. Pain is typical of herpes, chancroid, and tularemia, whereas donovanosis ulcers are usually painless. Ulcer base and borders can help narrow the differential: Behçet ulcers may be yellow and necrotic, chancroid bases are often necrotic, donovanosis can appear beefy red with hypertrophy, and syphilitic and herpetic ulcers may have cleaner bases; chancroid ulcers are classically nonindurated with irregular erythematous edges, syphilitic ulcers are indurated, and herpetic ulcers often have erythematous borders. Primary syphilis more often produces a solitary lesion, while chancroid often causes multiple ulcers of varying size. Behçet disease can cause recurrent, multiple genital ulcers involving scrotum or vulva and may be accompanied by recurrent oral ulcers and skin or eye disease, which may not occur simultaneously. Linear burrows suggest scabies, and reddish specks may reflect crab louse excreta. Urethral discharge suggests gonorrhea or reactive arthritis. In adults with genital lesions, inguinal lymphadenopathy supports consideration of chancroid, LGV, syphilis, herpes, lymphoma, or tuberculosis. LGV ulcers may be unnoticed and heal spontaneously, followed weeks later by painful inguinal lymphadenopathy and systemic symptoms, and untreated disease can progress to elephantiasis-like genital distortion. Lymphadenopathy tends to be unilateral in chancroid and LGV and more often bilateral in genital herpes. Painful perianal ulcers or mucosal ulcers seen on anoscopy should be treated presumptively for HSV and LGV. Molluscum contagiosum causes mildly contagious umbilicated papules up to about 1 cm, and advanced HIV may cause widespread or large lesions. Tuberculous genital lesions may appear as chronic minimally painful red, firm, nodular sores. Clinical appearance alone is often insufficient for diagnosis.
Diagnostic Tests and Interpretation
Laboratory Studies
All patients with genital, anal, or perianal ulcers should receive syphilis serology with dark-field examination when available, HSV testing by culture or PCR or type-specific serology, and HIV testing. If suspicion and culture capacity exist, obtain H. ducreyi culture for chancroid. Donovanosis can be supported by identifying intracellular Donovan bodies on Giemsa or Wright stain from lesion scrapings or biopsy, with biopsy favored when malignancy is possible. Chancroid culture can be sensitive but is limited by availability of selective media; a probable diagnosis relies on painful ulcers typical of chancroid with negative testing for syphilis and HSV. LGV diagnosis is supported by serology or by isolating C. trachomatis with confirmation of L1–L3 serovars. Molluscum can be confirmed by histology and electron microscopy. Chancres may be missed by patients, and early syphilis serology can be falsely negative; when diagnosis is uncertain or cancer is possible, biopsy is indicated.
Treatment
Medications
Chancroid can be treated with single-dose azithromycin 1 g orally or ceftriaxone 250 mg intramuscularly. Condylomata acuminata have no single best therapy; options include imiquimod 5% cream three times weekly for up to 16 weeks or podofilox 0.5% solution or gel twice daily for three days followed by one day off, repeated in cycles. Donovanosis can be treated for more than three weeks with trimethoprim-sulfamethoxazole, tetracycline, or doxycycline. Genital herpes is treated with acyclovir, famciclovir, or valacyclovir for 7–10 days, with intravenous acyclovir for severe disease. Tuberculous genital lesions require systemic antituberculosis therapy. LGV is treated with doxycycline 100 mg twice daily for 21 days. Molluscum contagiosum can be managed with lesion destruction via desiccation, cryotherapy, or curettage.
Complementary and Alternative Therapies
Alternative chancroid regimens include erythromycin for seven days or ciprofloxacin for three days. Wart management can include cryosurgery, excision, electrosurgery, or laser therapy. Donovanosis alternatives include prolonged ciprofloxacin, erythromycin, or chloramphenicol. LGV can also be treated with erythromycin four times daily for 21 days.
Ongoing Care and Follow-Up
Patients should be encouraged to have sexual partners evaluated and treated. HIV testing should be performed at diagnosis and repeated with syphilis serology about three months later if initially negative. Consider cervical cytology screening for patients evaluated for sexually transmitted infections who have not had a Pap smear within the past year, and counsel patients with HPV on the need for ongoing screening.
Pediatric Considerations
Sexually transmitted genital lesions in a child require evaluation for sexual abuse.
Complications
Untreated primary syphilis can disseminate and progress to secondary disease within weeks. Chancroid, genital herpes, and syphilis increase susceptibility to HIV transmission.
- Published on
Infectious Diseases and Microbiology: Fever of Unknown Origin
Basics
Description
Fever of unknown origin (FUO) describes persistent fever that lasts longer than expected for a typical acute febrile illness and is meant to exclude self-limited infections, conditions identified on basic initial testing, and benign fevers below 38.3°C. Current criteria, revised from the 1961 Petersdorf and Beeson definition, require illness duration of at least three weeks, documented temperatures above 38.3°C on multiple occasions, and no diagnosis despite a thorough evaluation. Durack and Street proposed FUO subtypes reflecting differing causes and workups: classical FUO, immune-deficient FUO, healthcare-associated FUO, and HIV-related FUO. Using this framework, immune-deficient patients, hospitalized patients who were afebrile before admission, and patients with HIV may meet FUO criteria after three to five inpatient days of evaluation with 48 hours of negative cultures.
Approach to the Patient
FUO is clinically difficult for both patients and clinicians, and management centers on identifying a cause, reaching a diagnosis efficiently and safely with appropriate testing, and initiating targeted therapy once a diagnosis is established or, when necessary, performing a therapeutic trial. Evaluation should be individualized to avoid both excessive testing for unlikely causes and missed evaluation of likely ones, so rigid algorithms are discouraged. Key aims are to confirm true fever and define its pattern, assess illness tempo and severity, look for localizing symptoms, place the illness in context of comorbidities and medications, and identify exposure risks such as travel, occupational and sexual history, animal contact, vaccination status, and intravenous drug use. Minimum baseline evaluation should include detailed history, repeated physical examination, complete blood count with smear, differential and platelets, routine chemistries including liver enzymes, LDH and bilirubin, urinalysis with microscopy and culture, chest radiograph, ESR and CRP, ANA, rheumatoid factor and anti-CCP, three sets of blood cultures obtained off antibiotics, tuberculosis testing with TST or IGRA, CT abdomen and pelvis, and infectious serologies guided by the clinical scenario.
Special Populations
Geriatric Considerations
Consider polymyalgia rheumatica and recognize that the distribution of undiagnosed etiologies differs in older adults.
Pediatric Considerations
Herpesviruses HHV-6/7/8 are common in infants and children. Ultrasound is preferred over CT to limit radiation and because pediatric imaging resolution is favorable. Connective tissue disease and neoplasia are uncommon under 12 months, Kawasaki disease is common under 5 years, Still’s disease often affects children and young adults, and arthritis in children should be treated as a marker of potentially serious disease. Periodic fever and other entities to consider include hyper-IgD syndrome, cyclic neutropenia, and nephroma.
Pregnancy Considerations
Pregnancy increases venous thromboembolism risk. Consider septic pelvic thrombophlebitis after obstetric surgery, sexually transmitted infections including HIV and syphilis, and pyometra.
Epidemiology
True FUO is uncommon. Reported etiologic frequencies vary by population, geography, institution, age, local disease prevalence, and practice patterns. Over time, the proportion of infectious and malignant causes has decreased while the proportion of undiagnosed cases has increased.
Diagnosis
FUO evaluation relies on iterative history-taking, repeated examinations, laboratory studies, and imaging.
History
History should cover alcohol use, medications, occupational and sexual exposures, pets, travel, family conditions, and prior illnesses. Although fever patterns are described for many disorders, truly distinctive patterns are rare in practice; classic patterns such as malaria are uncommon in many settings, and patterns considered characteristic for other diseases, such as Pel–Ebstein fever in lymphoma, are infrequently observed.
Physical Examination
Repeated comprehensive examination is central and should specifically assess the oropharynx for dental abscess, thyroid for thyroiditis, temporal regions for arteritis, cardiac auscultation for murmurs suggesting endocarditis or atrial myxoma, skin for vasculitis and Whipple disease clues, all wounds and vascular access sites with dressings removed for inspection, regional lymph nodes, and the genitoperineal region, sometimes requiring rectal or vaginal examination. Relative bradycardia can be a clue but is nonspecific and occurs in diverse conditions including brucellosis, drug fever, factitious fever, hepatitis A, Legionella infection, leptospirosis, malignancy, psittacosis, subacute necrotizing lymphadenitis, and typhoid fever. Fever from solid tumors and many connective tissue diseases may abate with NSAIDs, whereas fever from other causes may not. Symptoms such as sweats, chills, and weight loss do not reliably distinguish etiologies. Clues suggesting factitious fever include lack of tachycardia or tachypnea, temperatures exceeding 41°C, absent diurnal variation, and lack of sweating after defervescence.
Diagnostic Tests and Interpretation
Laboratory Studies
Noninvasive tests yield a diagnosis in roughly one-quarter of cases and include serologies for infectious and rheumatologic disease, biochemical markers such as ferritin for Still’s disease, and genetic markers such as those used for familial Mediterranean fever.
Imaging
Imaging is primarily used to localize targets for further evaluation. Abdominal CT has improved diagnostic yield when followed by invasive sampling, though false negatives can occur even with solid-organ abscesses. MRI is preferred when spinal or paraspinal pathology is suspected. Nuclear imaging with gallium-67 or indium-111 labeled leukocytes can sometimes help when infection or malignancy is suspected, but limitations include false-negative gallium scans in secondarily infected lesions, poor detection of splenic abscess due to background uptake, and low positive predictive value with indium studies. FDG PET/CT can help establish malignant, inflammatory, or infectious diagnoses in at least one-third of cases. If imaging and serologies are unrevealing, invasive investigations such as liver and bone marrow biopsy should be considered, and fewer than half of diagnoses are ultimately made via biopsy or laparotomy. Temporal artery biopsy is often high yield in older adults with markedly elevated ESR even without obvious local symptoms. Disseminated tuberculosis is a highly treatable lethal cause of FUO and warrants aggressive pursuit; TST and IGRA can be negative in up to half of cases, sputum smears are only intermittently positive, and confirmation often requires biopsy of lymph node, bone marrow, or liver. Excisional lymph node biopsy is helpful when nodes are enlarged, though inguinal nodes are commonly palpable and usually not diagnostically useful.
Differential Diagnosis
The major etiologic categories and approximate frequencies include infections, malignancies, connective tissue or inflammatory disorders, miscellaneous causes, and undiagnosed cases. Unusual presentations of common diseases and conditions that are difficult to confirm account for more FUO cases than truly rare diseases, and thinking in terms of FUO subtype helps prioritize causes.
Classical FUO
Common infectious drivers remain tuberculosis, bacterial endocarditis, and intraabdominal collections. Systemic bacterial causes include bartonellosis, brucellosis, Campylobacter infection, cat-scratch disease or bacillary angiomatosis, ehrlichiosis, gonococcemia, HACEK organisms, Legionella infection, leptospirosis, listeriosis, Lyme disease, meningococcemia, rat-bite fever, relapsing fever due to Borrelia recurrentis, salmonellosis including typhoid, syphilis, tularemia, and yersiniosis, along with chlamydial, fungal, parasitic, and viral infections. Localized infections include intravascular infections such as endocarditis, aortitis, catheter infections, septic jugular phlebitis, and vascular graft infection; intraabdominal infections such as appendicitis, cholangitis, cholecystitis, diverticulitis, and diverse abscesses (subphrenic, hepatic, splenic, pancreatic, perinephric, pelvic), mesenteric lymphadenitis, pelvic inflammatory disease, and pyometra; prosthesis-related infections involving joint prostheses, pacemakers, defibrillators, shunts, and vascular access; and other focal infections including dental, intracranial, pulmonary, mastoid, middle ear, sinus, prostatic, and wound infections. Common noninfectious causes include malignancies such as renal cell carcinoma, hepatocellular carcinoma, Hodgkin and non-Hodgkin lymphoma, colon cancer, leukemia, malignant histiocytosis, pancreatic cancer, and sarcoma; benign tumors such as atrial myxoma; inflammatory disorders such as adult Still’s disease, Behçet syndrome, and cryoglobulinemia; and miscellaneous conditions including neuroleptic malignant syndrome, hematoma, recurrent pulmonary embolism, aortic dissection, post–myocardial infarction fever syndromes, subacute thyroiditis, hyperthyroidism, adrenal insufficiency, drug fever, factitious fever, gout, pseudogout, hypersensitivity pneumonitis, stroke, familial Mediterranean fever, and pheochromocytoma.
Healthcare-Associated FUO
Infectious causes include intravascular catheter infection, septic thrombophlebitis, prosthetic device infection, deep postoperative wound infections and intraabdominal collections, C. difficile colitis that may present with ileus rather than diarrhea in severe disease, septic pelvic thrombophlebitis after obstetric or gynecologic surgery, acalculous cholecystitis, and ICU-associated sinusitis related to nasogastric tubes and endotracheal intubation. Miscellaneous causes include venous thromboembolism, drug fever often without rash or eosinophilia and commonly triggered by antimicrobials and multiple other medication classes, factitious fever, and postoperative inflammatory fever without a defined diagnosis.
Immune-Deficient FUO
Most cases are infectious, with pathogen identification in a large fraction, and the likely infections depend on the type and duration of immunodeficiency. Persistent fever can reflect progressive or relapsed malignancy in hematology-oncology patients, inflammatory causes such as graft-versus-host disease, or miscellaneous etiologies including venous thromboembolism, drug fever, and adrenal insufficiency.
HIV-Related FUO
Most cases are infectious, though FUO has decreased in the antiretroviral era due to fewer opportunistic infections, and likely etiologies depend strongly on CD4 count. Scenarios include HIV seroconversion illness, opportunistic infections such as mycobacterial disease, Pneumocystis jirovecii, cytomegalovirus, toxoplasmosis, histoplasmosis, and leishmaniasis, inflammatory syndromes such as immune reconstitution, Castleman disease, and hemophagocytic lymphohistiocytosis, malignancies such as lymphoma and Kaposi sarcoma, and drug fever.
Treatment
Medications
Management is determined by the underlying cause. If TST or IGRA is positive or if granulomatous disease with possible anergy is suspected, a therapeutic trial for tuberculosis is recommended and may be continued for up to six weeks; persistent fever beyond this period suggests an alternate diagnosis. Glucocorticoids and NSAIDs can suppress fever and obscure diagnosis while allowing infection to progress and should be avoided unless infection has largely been excluded. In severely immune-deficient patients, empiric antimicrobial therapy is often necessary because infections are common and associated with high mortality.
Ongoing Care and Follow-Up
Hospitalized patients with FUO require close monitoring for evolving symptoms or new physical findings that may provide diagnostic direction.
Basics
Description
Fever of unknown origin (FUO) describes persistent fever that lasts longer than expected for a typical acute febrile illness and is meant to exclude self-limited infections, conditions identified on basic initial testing, and benign fevers below 38.3°C. Current criteria, revised from the 1961 Petersdorf and Beeson definition, require illness duration of at least three weeks, documented temperatures above 38.3°C on multiple occasions, and no diagnosis despite a thorough evaluation. Durack and Street proposed FUO subtypes reflecting differing causes and workups: classical FUO, immune-deficient FUO, healthcare-associated FUO, and HIV-related FUO. Using this framework, immune-deficient patients, hospitalized patients who were afebrile before admission, and patients with HIV may meet FUO criteria after three to five inpatient days of evaluation with 48 hours of negative cultures.
Approach to the Patient
FUO is clinically difficult for both patients and clinicians, and management centers on identifying a cause, reaching a diagnosis efficiently and safely with appropriate testing, and initiating targeted therapy once a diagnosis is established or, when necessary, performing a therapeutic trial. Evaluation should be individualized to avoid both excessive testing for unlikely causes and missed evaluation of likely ones, so rigid algorithms are discouraged. Key aims are to confirm true fever and define its pattern, assess illness tempo and severity, look for localizing symptoms, place the illness in context of comorbidities and medications, and identify exposure risks such as travel, occupational and sexual history, animal contact, vaccination status, and intravenous drug use. Minimum baseline evaluation should include detailed history, repeated physical examination, complete blood count with smear, differential and platelets, routine chemistries including liver enzymes, LDH and bilirubin, urinalysis with microscopy and culture, chest radiograph, ESR and CRP, ANA, rheumatoid factor and anti-CCP, three sets of blood cultures obtained off antibiotics, tuberculosis testing with TST or IGRA, CT abdomen and pelvis, and infectious serologies guided by the clinical scenario.
Special Populations
Geriatric Considerations
Consider polymyalgia rheumatica and recognize that the distribution of undiagnosed etiologies differs in older adults.
Pediatric Considerations
Herpesviruses HHV-6/7/8 are common in infants and children. Ultrasound is preferred over CT to limit radiation and because pediatric imaging resolution is favorable. Connective tissue disease and neoplasia are uncommon under 12 months, Kawasaki disease is common under 5 years, Still’s disease often affects children and young adults, and arthritis in children should be treated as a marker of potentially serious disease. Periodic fever and other entities to consider include hyper-IgD syndrome, cyclic neutropenia, and nephroma.
Pregnancy Considerations
Pregnancy increases venous thromboembolism risk. Consider septic pelvic thrombophlebitis after obstetric surgery, sexually transmitted infections including HIV and syphilis, and pyometra.
Epidemiology
True FUO is uncommon. Reported etiologic frequencies vary by population, geography, institution, age, local disease prevalence, and practice patterns. Over time, the proportion of infectious and malignant causes has decreased while the proportion of undiagnosed cases has increased.
Diagnosis
FUO evaluation relies on iterative history-taking, repeated examinations, laboratory studies, and imaging.
History
History should cover alcohol use, medications, occupational and sexual exposures, pets, travel, family conditions, and prior illnesses. Although fever patterns are described for many disorders, truly distinctive patterns are rare in practice; classic patterns such as malaria are uncommon in many settings, and patterns considered characteristic for other diseases, such as Pel–Ebstein fever in lymphoma, are infrequently observed.
Physical Examination
Repeated comprehensive examination is central and should specifically assess the oropharynx for dental abscess, thyroid for thyroiditis, temporal regions for arteritis, cardiac auscultation for murmurs suggesting endocarditis or atrial myxoma, skin for vasculitis and Whipple disease clues, all wounds and vascular access sites with dressings removed for inspection, regional lymph nodes, and the genitoperineal region, sometimes requiring rectal or vaginal examination. Relative bradycardia can be a clue but is nonspecific and occurs in diverse conditions including brucellosis, drug fever, factitious fever, hepatitis A, Legionella infection, leptospirosis, malignancy, psittacosis, subacute necrotizing lymphadenitis, and typhoid fever. Fever from solid tumors and many connective tissue diseases may abate with NSAIDs, whereas fever from other causes may not. Symptoms such as sweats, chills, and weight loss do not reliably distinguish etiologies. Clues suggesting factitious fever include lack of tachycardia or tachypnea, temperatures exceeding 41°C, absent diurnal variation, and lack of sweating after defervescence.
Diagnostic Tests and Interpretation
Laboratory Studies
Noninvasive tests yield a diagnosis in roughly one-quarter of cases and include serologies for infectious and rheumatologic disease, biochemical markers such as ferritin for Still’s disease, and genetic markers such as those used for familial Mediterranean fever.
Imaging
Imaging is primarily used to localize targets for further evaluation. Abdominal CT has improved diagnostic yield when followed by invasive sampling, though false negatives can occur even with solid-organ abscesses. MRI is preferred when spinal or paraspinal pathology is suspected. Nuclear imaging with gallium-67 or indium-111 labeled leukocytes can sometimes help when infection or malignancy is suspected, but limitations include false-negative gallium scans in secondarily infected lesions, poor detection of splenic abscess due to background uptake, and low positive predictive value with indium studies. FDG PET/CT can help establish malignant, inflammatory, or infectious diagnoses in at least one-third of cases. If imaging and serologies are unrevealing, invasive investigations such as liver and bone marrow biopsy should be considered, and fewer than half of diagnoses are ultimately made via biopsy or laparotomy. Temporal artery biopsy is often high yield in older adults with markedly elevated ESR even without obvious local symptoms. Disseminated tuberculosis is a highly treatable lethal cause of FUO and warrants aggressive pursuit; TST and IGRA can be negative in up to half of cases, sputum smears are only intermittently positive, and confirmation often requires biopsy of lymph node, bone marrow, or liver. Excisional lymph node biopsy is helpful when nodes are enlarged, though inguinal nodes are commonly palpable and usually not diagnostically useful.
Differential Diagnosis
The major etiologic categories and approximate frequencies include infections, malignancies, connective tissue or inflammatory disorders, miscellaneous causes, and undiagnosed cases. Unusual presentations of common diseases and conditions that are difficult to confirm account for more FUO cases than truly rare diseases, and thinking in terms of FUO subtype helps prioritize causes.
Classical FUO
Common infectious drivers remain tuberculosis, bacterial endocarditis, and intraabdominal collections. Systemic bacterial causes include bartonellosis, brucellosis, Campylobacter infection, cat-scratch disease or bacillary angiomatosis, ehrlichiosis, gonococcemia, HACEK organisms, Legionella infection, leptospirosis, listeriosis, Lyme disease, meningococcemia, rat-bite fever, relapsing fever due to Borrelia recurrentis, salmonellosis including typhoid, syphilis, tularemia, and yersiniosis, along with chlamydial, fungal, parasitic, and viral infections. Localized infections include intravascular infections such as endocarditis, aortitis, catheter infections, septic jugular phlebitis, and vascular graft infection; intraabdominal infections such as appendicitis, cholangitis, cholecystitis, diverticulitis, and diverse abscesses (subphrenic, hepatic, splenic, pancreatic, perinephric, pelvic), mesenteric lymphadenitis, pelvic inflammatory disease, and pyometra; prosthesis-related infections involving joint prostheses, pacemakers, defibrillators, shunts, and vascular access; and other focal infections including dental, intracranial, pulmonary, mastoid, middle ear, sinus, prostatic, and wound infections. Common noninfectious causes include malignancies such as renal cell carcinoma, hepatocellular carcinoma, Hodgkin and non-Hodgkin lymphoma, colon cancer, leukemia, malignant histiocytosis, pancreatic cancer, and sarcoma; benign tumors such as atrial myxoma; inflammatory disorders such as adult Still’s disease, Behçet syndrome, and cryoglobulinemia; and miscellaneous conditions including neuroleptic malignant syndrome, hematoma, recurrent pulmonary embolism, aortic dissection, post–myocardial infarction fever syndromes, subacute thyroiditis, hyperthyroidism, adrenal insufficiency, drug fever, factitious fever, gout, pseudogout, hypersensitivity pneumonitis, stroke, familial Mediterranean fever, and pheochromocytoma.
Healthcare-Associated FUO
Infectious causes include intravascular catheter infection, septic thrombophlebitis, prosthetic device infection, deep postoperative wound infections and intraabdominal collections, C. difficile colitis that may present with ileus rather than diarrhea in severe disease, septic pelvic thrombophlebitis after obstetric or gynecologic surgery, acalculous cholecystitis, and ICU-associated sinusitis related to nasogastric tubes and endotracheal intubation. Miscellaneous causes include venous thromboembolism, drug fever often without rash or eosinophilia and commonly triggered by antimicrobials and multiple other medication classes, factitious fever, and postoperative inflammatory fever without a defined diagnosis.
Immune-Deficient FUO
Most cases are infectious, with pathogen identification in a large fraction, and the likely infections depend on the type and duration of immunodeficiency. Persistent fever can reflect progressive or relapsed malignancy in hematology-oncology patients, inflammatory causes such as graft-versus-host disease, or miscellaneous etiologies including venous thromboembolism, drug fever, and adrenal insufficiency.
HIV-Related FUO
Most cases are infectious, though FUO has decreased in the antiretroviral era due to fewer opportunistic infections, and likely etiologies depend strongly on CD4 count. Scenarios include HIV seroconversion illness, opportunistic infections such as mycobacterial disease, Pneumocystis jirovecii, cytomegalovirus, toxoplasmosis, histoplasmosis, and leishmaniasis, inflammatory syndromes such as immune reconstitution, Castleman disease, and hemophagocytic lymphohistiocytosis, malignancies such as lymphoma and Kaposi sarcoma, and drug fever.
Treatment
Medications
Management is determined by the underlying cause. If TST or IGRA is positive or if granulomatous disease with possible anergy is suspected, a therapeutic trial for tuberculosis is recommended and may be continued for up to six weeks; persistent fever beyond this period suggests an alternate diagnosis. Glucocorticoids and NSAIDs can suppress fever and obscure diagnosis while allowing infection to progress and should be avoided unless infection has largely been excluded. In severely immune-deficient patients, empiric antimicrobial therapy is often necessary because infections are common and associated with high mortality.
Ongoing Care and Follow-Up
Hospitalized patients with FUO require close monitoring for evolving symptoms or new physical findings that may provide diagnostic direction.
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Infectious Diseases and Microbiology: Ear Pain
Basics
Description
Otalgia denotes pain originating in or perceived in the ear. Evaluation should consider patient age and associated symptoms such as sore throat, fever, headache, visual changes, and symptom duration. A systematic ear examination is essential, beginning with the auricle and external auditory meatus, followed by inspection of the auditory canal and tympanic membrane to guide the differential diagnosis. A complete head and neck examination may uncover lymphadenopathy, pharyngeal or nasal inflammation, thyroid disease, or dental and oral pathology. Cerumen can obstruct visualization of the tympanic membrane and should be gently removed when necessary. Any exudate within the auditory canal should be cultured. Pain elicited by movement of the pinna suggests otitis externa, foreign body, or impacted cerumen. Perichondritis, an infectious process of the outer ear cartilage, must be differentiated from relapsing polychondritis, a noninfectious rheumatologic condition.
Epidemiology
Approximately half of ear pain cases are referred from non-otologic sources. Acute otitis externa, commonly termed swimmer’s ear, occurs more frequently during summer months. Recurrent acute otitis media affects about one-fifth of children. Head and neck malignancies typically occur after age 50 but may present earlier, even without classic risk factors; several forms of nasopharyngeal carcinoma are associated with Epstein–Barr virus infection. Auricular cellulitis often follows minor trauma. Perichondritis usually develops after burns, trauma, or upper-ear piercings and is most commonly caused by Pseudomonas aeruginosa or Staphylococcus aureus. Chronic otitis externa often results from repeated minor trauma such as scratching or cotton swab use, and chronic middle-ear drainage may be mistaken for this condition. Malignant otitis externa is a destructive infection of the external canal and skull base.
Etiology
Ear pain is frequently referred because the ear receives sensory innervation from cranial nerves V, VII, VIII, IX, and X. Referred otalgia may arise from dental disease, gingival abscesses, nasopharyngeal or laryngeal inflammation or tumors, sinusitis, temporomandibular joint disorders, tonsillitis, tongue lesions, cervical spine disease, neural irritation such as trigeminal neuralgia or acoustic neuroma, gastroesophageal reflux in infants, thyroiditis, lateral sinus thrombosis, posterior fossa inflammation, or medication effects. Primary ear pathology causing otalgia includes acute or chronic otitis media, tympanic membrane rupture, anterior canal wall fracture, mastoiditis, Ménière disease, and eustachian tube dysfunction. Malignant otitis externa is almost always due to Pseudomonas aeruginosa. Otalgia may also accompany migraine, atypical facial pain, and herpes simplex infection of cranial nerves V, VII, or IX. Herpes zoster affecting the external auditory canal may produce ipsilateral facial paralysis, known as Ramsay Hunt syndrome, from involvement of the geniculate ganglion. Facial nerve palsy may also occur with Lyme disease. Neoplasms of the infratemporal fossa may present solely with ear pain. Acute otitis externa is most often caused by Pseudomonas aeruginosa, Staphylococcus aureus, or streptococcal species, with swimming and canal trauma as major risk factors.
Diagnosis
Clinical Manifestations
Auricular cellulitis presents with a swollen, erythematous, warm, mildly tender ear. Perichondritis causes marked swelling, redness, heat, and severe tenderness of the pinna with relative sparing of the lobule. Chronic otitis externa more commonly causes itching than pain. Nasopharyngeal carcinoma may be asymptomatic early but often produces unilateral serous otitis media from eustachian tube obstruction, nasal blockage, or epistaxis, and advanced disease may cause cranial nerve palsies, especially involving nerves III, IV, VI, and VII. Malignant otitis externa typically affects elderly patients with diabetes or individuals with HIV and presents with severe otalgia, otorrhea, possible hearing loss, tender pinna, trismus from temporomandibular involvement, and sometimes cranial nerve palsies, most often of nerve VII. Fever and weight loss are uncommon. Examination reveals canal edema, erythema, purulent discharge, debris, and granulation tissue. Vesicular lesions in the external canal suggest herpes zoster and warrant evaluation for facial nerve palsy. Hearing loss with abnormal tympanic membrane findings indicates serous or bacterial otitis media or cholesteatoma. Nasal polyps, marked septal deviation, or nasopharyngeal tumors may be associated with otitis media.
Physical Examination
Findings such as an erythematous canal with discharge, preauricular lymphadenopathy, and pain on tragal or pinna manipulation suggest otitis externa. Fever, irritability in children, and a bulging or erythematous tympanic membrane with loss of the cone of light indicate otitis media, sometimes with canal pus if perforation is present. Altered mental status or meningeal signs such as headache and neck stiffness indicate possible central nervous system involvement and require urgent management.
Diagnostic Tests and Interpretation
Laboratory Studies
Peripheral leukocytosis is uncommon in malignant otitis externa, whereas erythrocyte sedimentation rate is typically elevated. Cerebrospinal fluid analysis may occasionally show pleocytosis and increased protein.
Imaging
Dental pathology can be assessed with panoramic radiography. In malignant otitis externa, CT of the temporal bone or mastoid often demonstrates bony erosion and new bone formation, while MRI more accurately defines soft-tissue extension and skull-base involvement.
Treatment
Medications
Acute otitis externa is managed with careful canal cleaning and topical therapy using antiseptics or antibiotic drops such as polymyxin–neomycin, along with counseling on ear hygiene and water avoidance. Malignant otitis externa requires urgent otolaryngology consultation and prolonged antipseudomonal therapy with agents such as cefepime, ceftazidime, carbapenems, or fluoroquinolones, typically for at least three to four weeks and longer if bone involvement is present. Auricular cellulitis is treated with warm compresses and intravenous antibiotics targeting staphylococci and streptococci. Severe perichondritis requires extended antibiotic therapy, often with agents such as piperacillin–tazobactam or nafcillin combined with ciprofloxacin, and may benefit from incision and drainage. Ramsay Hunt syndrome is treated with acyclovir and corticosteroids, and early therapy improves facial nerve outcomes; ophthalmologic evaluation is recommended to assess ocular involvement.
Ongoing Care and Follow-Up
Referral to an otolaryngologist is advised when ear pain persists despite appropriate initial evaluation and management.
Complications
Otitis media can lead to mastoiditis, epidural abscess, dural venous sinus thrombosis, meningitis, or brain abscess. Malignant otitis externa may extend to the cavernous sinus or contralateral petrous apex, and although meningitis and brain abscess are uncommon, they are serious potential sequelae.
Basics
Description
Otalgia denotes pain originating in or perceived in the ear. Evaluation should consider patient age and associated symptoms such as sore throat, fever, headache, visual changes, and symptom duration. A systematic ear examination is essential, beginning with the auricle and external auditory meatus, followed by inspection of the auditory canal and tympanic membrane to guide the differential diagnosis. A complete head and neck examination may uncover lymphadenopathy, pharyngeal or nasal inflammation, thyroid disease, or dental and oral pathology. Cerumen can obstruct visualization of the tympanic membrane and should be gently removed when necessary. Any exudate within the auditory canal should be cultured. Pain elicited by movement of the pinna suggests otitis externa, foreign body, or impacted cerumen. Perichondritis, an infectious process of the outer ear cartilage, must be differentiated from relapsing polychondritis, a noninfectious rheumatologic condition.
Epidemiology
Approximately half of ear pain cases are referred from non-otologic sources. Acute otitis externa, commonly termed swimmer’s ear, occurs more frequently during summer months. Recurrent acute otitis media affects about one-fifth of children. Head and neck malignancies typically occur after age 50 but may present earlier, even without classic risk factors; several forms of nasopharyngeal carcinoma are associated with Epstein–Barr virus infection. Auricular cellulitis often follows minor trauma. Perichondritis usually develops after burns, trauma, or upper-ear piercings and is most commonly caused by Pseudomonas aeruginosa or Staphylococcus aureus. Chronic otitis externa often results from repeated minor trauma such as scratching or cotton swab use, and chronic middle-ear drainage may be mistaken for this condition. Malignant otitis externa is a destructive infection of the external canal and skull base.
Etiology
Ear pain is frequently referred because the ear receives sensory innervation from cranial nerves V, VII, VIII, IX, and X. Referred otalgia may arise from dental disease, gingival abscesses, nasopharyngeal or laryngeal inflammation or tumors, sinusitis, temporomandibular joint disorders, tonsillitis, tongue lesions, cervical spine disease, neural irritation such as trigeminal neuralgia or acoustic neuroma, gastroesophageal reflux in infants, thyroiditis, lateral sinus thrombosis, posterior fossa inflammation, or medication effects. Primary ear pathology causing otalgia includes acute or chronic otitis media, tympanic membrane rupture, anterior canal wall fracture, mastoiditis, Ménière disease, and eustachian tube dysfunction. Malignant otitis externa is almost always due to Pseudomonas aeruginosa. Otalgia may also accompany migraine, atypical facial pain, and herpes simplex infection of cranial nerves V, VII, or IX. Herpes zoster affecting the external auditory canal may produce ipsilateral facial paralysis, known as Ramsay Hunt syndrome, from involvement of the geniculate ganglion. Facial nerve palsy may also occur with Lyme disease. Neoplasms of the infratemporal fossa may present solely with ear pain. Acute otitis externa is most often caused by Pseudomonas aeruginosa, Staphylococcus aureus, or streptococcal species, with swimming and canal trauma as major risk factors.
Diagnosis
Clinical Manifestations
Auricular cellulitis presents with a swollen, erythematous, warm, mildly tender ear. Perichondritis causes marked swelling, redness, heat, and severe tenderness of the pinna with relative sparing of the lobule. Chronic otitis externa more commonly causes itching than pain. Nasopharyngeal carcinoma may be asymptomatic early but often produces unilateral serous otitis media from eustachian tube obstruction, nasal blockage, or epistaxis, and advanced disease may cause cranial nerve palsies, especially involving nerves III, IV, VI, and VII. Malignant otitis externa typically affects elderly patients with diabetes or individuals with HIV and presents with severe otalgia, otorrhea, possible hearing loss, tender pinna, trismus from temporomandibular involvement, and sometimes cranial nerve palsies, most often of nerve VII. Fever and weight loss are uncommon. Examination reveals canal edema, erythema, purulent discharge, debris, and granulation tissue. Vesicular lesions in the external canal suggest herpes zoster and warrant evaluation for facial nerve palsy. Hearing loss with abnormal tympanic membrane findings indicates serous or bacterial otitis media or cholesteatoma. Nasal polyps, marked septal deviation, or nasopharyngeal tumors may be associated with otitis media.
Physical Examination
Findings such as an erythematous canal with discharge, preauricular lymphadenopathy, and pain on tragal or pinna manipulation suggest otitis externa. Fever, irritability in children, and a bulging or erythematous tympanic membrane with loss of the cone of light indicate otitis media, sometimes with canal pus if perforation is present. Altered mental status or meningeal signs such as headache and neck stiffness indicate possible central nervous system involvement and require urgent management.
Diagnostic Tests and Interpretation
Laboratory Studies
Peripheral leukocytosis is uncommon in malignant otitis externa, whereas erythrocyte sedimentation rate is typically elevated. Cerebrospinal fluid analysis may occasionally show pleocytosis and increased protein.
Imaging
Dental pathology can be assessed with panoramic radiography. In malignant otitis externa, CT of the temporal bone or mastoid often demonstrates bony erosion and new bone formation, while MRI more accurately defines soft-tissue extension and skull-base involvement.
Treatment
Medications
Acute otitis externa is managed with careful canal cleaning and topical therapy using antiseptics or antibiotic drops such as polymyxin–neomycin, along with counseling on ear hygiene and water avoidance. Malignant otitis externa requires urgent otolaryngology consultation and prolonged antipseudomonal therapy with agents such as cefepime, ceftazidime, carbapenems, or fluoroquinolones, typically for at least three to four weeks and longer if bone involvement is present. Auricular cellulitis is treated with warm compresses and intravenous antibiotics targeting staphylococci and streptococci. Severe perichondritis requires extended antibiotic therapy, often with agents such as piperacillin–tazobactam or nafcillin combined with ciprofloxacin, and may benefit from incision and drainage. Ramsay Hunt syndrome is treated with acyclovir and corticosteroids, and early therapy improves facial nerve outcomes; ophthalmologic evaluation is recommended to assess ocular involvement.
Ongoing Care and Follow-Up
Referral to an otolaryngologist is advised when ear pain persists despite appropriate initial evaluation and management.
Complications
Otitis media can lead to mastoiditis, epidural abscess, dural venous sinus thrombosis, meningitis, or brain abscess. Malignant otitis externa may extend to the cavernous sinus or contralateral petrous apex, and although meningitis and brain abscess are uncommon, they are serious potential sequelae.
