CONTENTS

• Nonzoonotic atypical pneumonias:
  • Legionella
  • Mycoplasma
  • Chlamydia pneumoniae
• Zoonotic atypical pneumonias:
  • Chlamydia psittaci (psittacosis)
  • Francisella tularensis (tularemia)*
  • Coxiella burnetii (Q fever)*
  • *May fail to respond to azithromycin; doxycycline will cover.
• Leptospirosis
• Questions & discussion

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legionella

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diagnostic clues

• 🔍 Lack of upper respiratory features.
• 🔍 Extrapulmonary involvement (e.g., gastrointestinal, neurological).
• 🔍 Labs:
  • Procalcitonin is usually moderately elevated.
  • C-Reactive Protein is usually markedly elevated.
  • Ferritin may be markedly elevated.
  • Urinary legionella antigen is usually positive.
• 🔍 Radiologically, often causes multi-lobar consolidation.
• 🔍 Illness severity is high.

epidemiology

• Legionella causes ~8% of severe community-acquired pneumonia, so this is regularly encountered in the ICU. (27276986)
• Legionella may sometimes colonize water sources, leading to epidemics (including within hospitals).
• Legionella has a seasonal pattern, with highest activity in warm, rainy, and humid conditions. (29490174)
• Risk factors:
  • Impaired T-cell immunity:
    • HIV.
    • Immunosuppressive medications (e.g., steroid, TNF-inhibitors).
    • Transplantation (especially high risk, may be sentinel victims in nosocomial outbreaks).
    • Hematologic malignancy.
  • COPD, smoking.
  • Malignancy.
  • Alcoholism.
  • Diabetes.
  • End-stage renal disease.
  • Heart failure.
  • Older age (overall ~80% of cases occur in patients >50 years old). (27276986)

clinical presentation

• Incubation is typically ~2-10 days. (27276986)
• Brief prodrome: Weakness, malaise, anorexia, headache.
• Marked systemic illness (high fevers, rigors, headache, myalgias, arthralgias).
  • Absence of fever argues strongly against Legionella infection. (28159178)
• Pneumonia:
  • Cough is productive in half of patients (usually nonpurulent; may be blood-streaked).
  • Dyspnea.
  • Pleuritic chest pain may be prominent.
• Neurological: Legionella has historically been associated with various neurological syndromes, but in retrospect some of these may not have been true causative relationships. Many neurologic complications (e.g., delirium) correlate with overall disease severity. Since Legionella often causes severe disease, it may be more likely to cause a variety of nonspecific neurologic complications. Potential neurological complications include:
  • Severe pneumonia with delirium: Overall rates of delirium appear to be similar to those of other patients with severe pneumonia. (27979685) Legionellosis may be associated with alcoholism, so the possibility of Wernicke's encephalopathy should also be considered.
  • MERS (mild encephalopathy with reversible splenial lesion). 📖(30782478, 22886060, 26631897)
  • Guillain-Barre syndrome. 📖
  • ADEM (acute disseminated encephalomyelitis). 📖
• Other organ involvement which may occur:
  • Gastrointestinal: watery diarrhea is most common, abdominal pain, nausea/vomiting.
  • Renal: rhabdomyolysis, acute kidney injury. (Murray 2022)

radiology

• Consolidation in a lobar pattern:
  • Initially, peripheral sublobar consolidation may be seen. These can rapidly progress to complete lobar involvement, which often occurs within a few days.
    • 💡 Rapid radiographic progression may suggest Legionella. (Rosado-de-Christenson 2022) Progression can occur even after therapy has been initiated.
  • On CT scan, areas of consolidation may be surrounded by ground-glass opacification that may have a subtle crazy-paving appearance. (Rosado-de-Christenson 2022) These areas of ground-glass opacification subsequently become consolidated as the disease advances. 
  • Consolidation may occasionally be configured as a solitary sphere (“round pneumonia”) or as multiple nodules/masses.
• Pleural effusion occurs in most patients, but shouldn't be massive. (28159175)
• Features that usually aren't seen:
  • Mild mediastinal and hilar lymphadenopathy can be seen on CT scan in about half of patients. (Rosado-de-Christenson 2022) However, bulky lymphadenopathy would suggest an alternative diagnosis. (28159175)
  • Cavitation and/or abscess formation is rare (~1-6% of patients), but can occur more often in the context of immunocompromise. (Murray 2022; Walker 2019) If cavitation occurs rapidly (within 72 hours), this argues strongly against legionella. (28159175)
  • Reversed halo sign may rarely be seen. (28159175)

laboratory tests

• General laboratory tests may sometimes reveal:
  • Hyponatremia.
  • Rhabdomyolysis.
  • Microscopic hematuria. (28159178)
• Inflammatory markers:
  • Procalcitonin is generally moderately elevated (interquartile range 2-6 ug/L). (24813862)
  • C-reactive protein is generally markedly elevated (interquartile range 200-450 mg/L). (24813862)
  • Ferritin may be markedly elevated (with extremely rare progression to full-blown hemophagocytic lymphohistiocytosis). (28159178)
• Sputum may show neutrophils, without any organisms.
• Urinary antigen detection for serogroup 1 only:
  • Legionella serogroup 1 causes ~85% of infections. (27276986) Performance for this serogroup is good (sensitivity ~75%, specificity ~99%). (24626238) However, other serogroups are missed, so the overall sensitivity for any Legionella infection might be ~70%. (24813862) Other gram-negative bacteria can generate a false positive test result. (32561442)
  • Antigen appears in urine within three days of illness, and may subsequently persist for ~6 weeks.
• PCR may be utilized on respiratory specimens (e.g., tracheal aspirate). This may be the best single assay for Legionella (with sensitivity of 80% and specificity of 90%). (24813862)
• (Legionella culture)
  • Legionella requires a dedicated culture medium, so it must be specifically ordered.
  • Sensitivity may be ~65%, but specificity is high. (24813862)
  • An incubation time of 3-5 days is required (plus transport time if this is a send-out test at your hospital).

treatment

• Antibiotics:
  • Fluoroquinolones (typically levofloxacin) or macrolides (e.g., azithromycin) are preferred therapy. Azithromycin seems to be as effective as fluoroquinolones, but should be dosed appropriately (e.g., 500 mg IV daily for 10 days). Given a reduced risk of neuromuscular side effects as compared to fluoroquinolones, high-dose IV azithromycin may be preferred.
  • There is no good evidence that combination therapy is superior to monotherapy with either azithromycin or levofloxacin.
  • Doxycycline is a third-line option (after azithromycin and levofloxacin).
  • Duration of therapy is unclear (perhaps 7 days for patients who respond well, or longer in patients with immunosuppression or unusually severe disease).
• Steroid: Legionella typically causes severe systemic inflammation, suggesting an increased role for adjunctive steroid therapy (more on steroid treatment for CAP here: 📖).
• Respiratory support: Patients may tend to deteriorate precipitously during the first 1-2 days following admission. Close monitoring is appropriate, with consideration for early escalation to ICU-level care as indicated.

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mycoplasma

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diagnostic clues

• 🔍 Preceding upper respiratory symptoms (rhinorrhea, sore throat, conjunctivitis).
• 🔍 Extrapulmonary involvement (e.g., dermatologic, hemolytic anemia).
• 🔍 Radiologically, often causes bronchopneumonia pattern.
• 🔍 Illness severity is usually mild.

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epidemiology of mycoplasma

• Mycoplasma may be the most common cause of atypical pneumonia. (33036113) However, only ~10% of infected people develop pneumonia. (29264006)
• Mycoplasma frequently occurs in young, healthy people. It may cause outbreaks among young adults living in close quarters, healthcare facilities, or nursing homes. Alternatively, <5% of cases occur in the elderly.
• Transmission occurs person-to-person via respiratory droplets. Mycoplasma may be seen year round, but is most frequent in the fall and winter.
• Risk factors for severe pneumonia:
  • Asplenia.
  • Hypogammaglobulinemia.
  • Underlying asthma or COPD. (29904437)
  • Smoking.
  • Sickle cell anemia (due to the occurrence of cold agglutinins).
• Immunity wanes over a period of ~2-10 years. Thus, multiple re-infections can occur during anyone's lifespan. (29264006) 

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clinical presentation of mycoplasma

chronicity

• Incubation is 1-3 weeks. (27276986)
• Illness may be prolonged, with resolution over 1-2 weeks.

clinically, mycoplasma resembles a viral infection

• Progresses from upper to lower respiratory tract symptoms.
• Initial symptoms involve the upper airway: sore throat, rhinorrhea, and conjunctivitis.
• Cervical lymphadenopathy may occur.
• Systemic toxicity is usually mild (e.g., low-grade fever, headache, arthralgias).

pulmonary

• Mycoplasma may cause acute bronchitis and/or bronchopneumonia.
• Cough (93-100%): (29264006)
  • Usually nonproductive.
  • May have frequent, prolonged cough with chest muscle soreness.
• Pneumonia is usually self-limiting, and only rarely requires ICU admission. Mycoplasma has been known as “walking pneumonia” because patients are generally able to carry out their activities of daily living. (27960206) However, fulminant cases tend to occur in young and otherwise healthy patients. (27276986)

extrapulmonary manifestations:

Mucocutaneous manifestations occur in ~25% of patients (may be confused with a drug reaction), including: (26653193)

• Maculopapular or vesicular rash.
• Erythema multiforme.
• Erythema nodosum.
• Cutaneous leukocytoclastic vasculitis.
• Mycoplasma pneumoniae-associated mucositis (limited to the mouth and eyes), aka reactive infectious mucocutaneous eruption (RIME). (26653193)
• Steven-Johnson syndrome, toxic epidermal necrolysis.
• Raynaud phenomenon. (27960206)

Hematologic:

• Hemolytic anemia:
  • Often arises after ~2 weeks of infection, due to production of cold hemagglutinins.
  • Occurs in ~50% of patients, but it is usually subclinical or mild. In the context of underlying hematologic disorders (e.g., sickle cell anemia), hemolysis may have severe consequences.
  • Laboratory testing should show a positive cold agglutinin titer and a positive direct antiglobulin test (DAT) (positive for complement C3d, but negative for IgG).
  • Hemolysis usually resolves spontaneously after ~4-6 weeks. Steroid may be utilized, but its efficacy is unclear.
• Hemophagocytic lymphohistiocytosis may rarely occur. (29264006)

Gastrointestinal:

• Nausea, vomiting, abdominal pain, and/or diarrhea can occur (but this is unusual). (29264006)
• Acute hepatitis may occur 7-10 days after the onset of fever. (28159161, 29264006)

Neurologic:

• Neurologic complications occur in ~5% of hospitalized patients with Mycoplasma pneumoniae infection. (Louis 2021) These are likely immune-mediated (aka parainfectious or postinfectious). They often begin days to weeks following respiratory infection. (33522738)
• Clinical syndromes associated with Mycoplasma:
  • Meningoencephalitis, encephalitis, or aseptic meningitis.
  • Transverse myelitis, usually in the context of ADEM (acute disseminated encephalomyelitis).📖
  • Guillain-Barre syndrome.📖
  • Cranial nerve palsies, including optic neuritis.
• Treatment: The role of antibiotics is dubious, since neurologic conditions are generally postinfectious. Management often centers around immunomodulatory therapies (e.g., steroid and/or IVIG). Treatment is based on the clinical manifestation (e.g., Guillain-Barre syndrome is managed with standard treatments for that disorder).

Other extrapulmonary manifestations: (29264006)

• Cardiac: myocarditis, pericarditis, Kawasaki disease.
• Glomerulonephritis.
• Rhabdomyolysis.
• Arthritis.

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radiology of mycoplasma

Radiologic findings are often disproportionately dramatic, as compared to the degree of clinical respiratory failure. Furthermore, clinical improvement may be accompanied by worsening on chest radiology. (33036113) Overall, treatment decisions should be based upon clinical criteria, rather than radiology.

chest radiograph

• May show an interstitial, reticular pattern.
• May show a bronchopneumonia pattern (with bilateral, patchy infiltrates).

CT findings

• Bronchopneumonia is usually seen, which may include: (Rosado-de-Christenson 2022)
  • Ground-glass opacities (86%).
  • Centrilobular nodules of 3-10 mm size (89%), including a tree-in-bud pattern.
  • Bronchial wall thickening.
  • Interlobular septal thickening.
• Lymphadenopathy (10%). (Rosado-de-Christenson 2022)
• Pleural effusion (~10%). (Rosado-de-Christenson 2022)

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laboratory tests for mycoplasma

nonspecific studies

• Sputum may reveal neutrophils without bacteria (Mycoplasma lacks a cell wall, so it cannot be seen on Gram stain).
• An elevated ratio of CRP (C-Reactive Protein) to procalcitonin may help differentiate Mycoplasma from typical pneumonias such as pneumococcal pneumonia. One study found that 73% of patients with Mycoplasma had a CRP/PCT ratio >400 mg/ug, whereas this was found in only 11% of patients with pneumococcus. (31128571)

specific tests

• PCR is the preferred test for active infection (the ordering code from Mayo Clinic is MPRP). This may be performed on bronchoalveolar lavage fluid or on nasopharyngeal aspirate. However, this isn't perfect. In some cases, a positive PCR may reflect colonization rather than invasive infection. (24626238)
• Serology may be negative in the first week of illness, so its use in directing therapy is dubious. (24626238) Additionally, IgM production may be inconsistent among adults. (36088100)

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treatment of mycoplasma

• Macrolides (e.g., azithromycin), doxycycline, or fluoroquinolones are all usually effective. (24626238)
  • Macrolide resistance is rising in some locales (e.g., as high as 97% in China), but currently seems to remain low in the United States. (27960206) Persistent fevers for >48 hours suggest macrolide resistance. (29264006)
  • Fluoroquinolones are generally not preferred, given potential neuromuscular toxicity. 📄
• Optimal duration of therapy is unknown. Persistent infection and clinical relapse are possible, which might argue for longer durations of therapy in sicker patients who have marginal response to therapy.
• Adjunctive steroid administration may be beneficial. (24813862)

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Chlamydia pneumoniae

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diagnostic clues

• 🔍 Prominent antecedent upper respiratory tract symptoms (especially sore throat, hoarseness).
• 🔍 Radiologically, often causes a single area of consolidation.
• 🔍 Illness severity is usually mild.

epidemiology

• Severe pneumonia can occur in the elderly. Chlamydia pneumoniae often affects patients with underlying obstructive airway disease (e.g., COPD, cystic fibrosis). (Walker 2019)
• The mode of transmission is thought to be person-to-person via respiratory secretions (with the potential for outbreaks, similar to Mycoplasma infection). (24626238) 

clinical presentation

• Clinical presentation generally resembles Mycoplasma infection.
• Incubation is ~21 days. (27276986)
• (1) Prominent antecedent upper respiratory tract symptoms, including sore throat, hoarseness, sinusitis, rhinorrhea. Laryngitis has been cited as feature that distinguishes Chlamydia from Mycoplasma or Legionella. (33835878)
• (2) Pneumonia phase:
  • Develops days to weeks after upper respiratory tract symptoms (biphasic illness).
  • Cough which is usually productive. (28159161)
  • Wheezing (60%). (28159161)
  • Pneumonia is usually mild, but can be severe in elderly patients with comorbidities.
• (3) Cough may persist for several weeks. (28159161)

radiology

• Most often there is a unilobar patchy consolidation, often in one of the lower lobes. (33835878)
• Progression to multilobar consolidation and effusion can occur. (33835878)
• Pleural effusions may be seen in ~25% of patients, but usually are small. (Walker 2019)

laboratory tests

• Leukocytosis is frequently absent.
• Specific diagnosis usually isn't obtained during acute infection. Serology can be performed, but this may take 6-8 weeks to become positive. (24626238) PCR is the preferred laboratory study, if available. 

treatment

• Doxycycline is the standard treatment, but azithromycin also has good activity.
• Fluoroquinolones have less activity against Chlamydophila spp. (24626238) 

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Chlamydia psittaci (psittacosis)

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diagnostic clues

• 🔍 Exposure to birds is an important clue.
• 🔍 Pharyngitis often occurs; otherwise the level of systemic illness may mimic that caused by Legionella.
• 🔍 Radiologically, resembles Chlamydia pneumoniae infection (often causes a single area of consolidation).
• 🔍 Splenomegaly may be a useful clue (seen in Psittacosis or Q-fever). (28159178)
• 🔍 Labs can reveal DIC and/or HLH (hemophagocytic lymphohistiocytosis).

epidemiology

• Chlamydia psittaci is common among wild and domestic birds worldwide. (24626238) 
• Psittacosis is spread in an airborne fashion, originating from bird feces. Even a few minutes exposure is sufficient. Dried organisms may remain viable for months.
• Exposure pattern:
  • ~70% due to a pet bird.
  • ~10% in poultry workers.
  • ~5% related to wild birds.
  • ~10% no recognized bird contact.

clinical presentation

• Overall, severe psittacosis shares many features with severe legionellosis. (27276986)
• Incubation: 1-2 weeks or longer (range from 5-40 days).
• Systemic symptoms are prominent:
  • Fever in nearly all patients.
  • Rigors in 60% of patients.
  • Night sweats, myalgias in most.
• Headache is often severe. This may be the chief complaint.
  • Encephalitis with cerebellar or cranial nerve dysfunction can occur.
• Pulmonary symptoms:
  • Cough is usually dry (may be productive of small amounts of mucoid or bloody sputum).
  • May require intubation.
• Pharyngitis and cervical lymphadenopathy often occur.
• GI: Diarrhea, icterus may be seen.
• Dermatologic:
  • Erythema nodosum.
  • Erythema multiforme.
  • Erythema marginatum.
  • Horder spots (faint macular rash).
  • Keratoconjunctivitis.
• Cardiovascular: Pericarditis, myocarditis, or endocarditis may occur.
• Hepatosplenomegaly may occur.

radiology

• Most often causes patchy or lobar consolidation, with a predilection for the lower lobes (similar to Chlamydia pneumoniae). (33835878)
• On CT scan, may see nodular infiltrates that are surrounded by ground-glass opacification (figure below).
• Pleural effusions are rare.

laboratory tests

• General laboratory tests:
  • DIC.
  • HLH (hemophagocytic lymphohistiocytosis) may occur. 📖
• Specific tests:
  • PCR is preferred, but often restricted to reference laboratories.
  • Serology is specific, but seroconversion may take time.

treatment

• Doxycycline is front-line therapy (100 mg BID for ~10 days).
• Azithromycin is second-line therapy, when doxycycline is contraindicated.
• (Efficacy of fluoroquinolones is unclear.)

pathophysiology

• C. psittaci is an obligate intracellular gram-negative bacterium.

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Francisella tularensis (tularemia)

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diagnostic clues

• 🔍 Epidemiology usually involves:
  • (1) Travel or residence in an endemic region.
  • (2) Exposure to animals or outdoors (e.g., ticks, deer fly bites, gardening, lawn mowing).
• 🔍 Pharyngitis or dermatologic features may suggest atypicality.
• 🔍 Radiologic features suggestive of tularemia may include a nodular pneumonia, or prominent lymphadenopathy.

epidemiology

• Tularemia is widely distributed in North America. Tularemia is endemic in some areas (especially Martha's Vineyard in Massachusetts, Arkansas, Oklahoma, Missouri, South Dakota, and Kansas). (24280916) The most recent data from the CDC is here: 🌊
• Tularemia may be spread via:
  • Ticks or deer fly bites.
  • Direct contact with animals (predominantly rabbits; but also rodents, cats, dogs, birds, sheep, foxes, horses).
  • Aerosolization (e.g., due to lawn mowing, gardening, soil, farms).
• Exposures may include:
  • Farmers.
  • Hunters.
  • Animal shearers, laboratory workers.
  • Landscapers.
• Pneumonia is most common in the spring to summer.

clinical presentation

• Following aerosol exposure, incubation is typically 2-7 days (with a range of 1-21 days).
  • In some cases, pneumonia may follow the development of ulceroglandular form of tularemia (which is marked by dermal ulceration with regional lymphadenopathy).
• Constitutional symptoms: high fever, severe headache, prominent myalgias, and shaking chills may occur. (Fishman 2023) Pharyngitis can occur, which may be misdiagnosed as mononucleosis. (23594007)
• Pneumonia may be severe:
  • Dry cough.
  • Dyspnea.
  • Occasional pleuritic chest pain.
  • Infiltrates may be unresponsive to usual antibiotic therapy.
• Dermatologic findings may also include:
  • Vesicular, urticarial, or maculopapular rashes.
  • Erythema multiforme.
  • Erythema nodosum.

radiology

• Radiologic findings may be disproportionately severe as compared to the clinical severity of illness.
• Parenchymal findings may vary: (33835878)
  • Consolidation may be patchy, lobar, or multilobar.
  • Pulmonary nodules may occur.
• Hilar and mediastinal lymphadenopathy is a prominent feature:
  • Ipsilateral hilar lymphadenopathy in 25-50%.
  • (Differential diagnosis of lymphadenopathy: 📖)
• Pleural effusion and empyema can occur.
  • Effusion may be serosanguinous or frankly bloody (which, among pulmonary infectious diseases, suggests tularemia or anthrax). (Fishman 2023)
• (Cavitation and bronchopleural fistula formation can rarely occur). (Walker 2019)

laboratory testing is largely unhelpful

• Francisella tularensis is a gram negative coccobacillus.
• Blood cultures are generally negative. If tularemia is suspected, the lab should be notified to avoid aerosol spread to laboratory workers.
• Serology >1:160 is supportive, but may be falsely negative early in infection. Four-fold rise in convalescent sera (1-5 weeks later) may have higher sensitivity. (Fishman 2023) There may be serological cross-reactivity with Brucella or Yersinia species.
• Pleural effusions are usually exudative, often with a lymphocytic predominance.
• PCR is increasingly utilized (but not widely available).

treatment

• Gentamicin therapy is preferred for more severe illness. 💉
• For milder disease, doxycycline or ciprofloxacin may be utilized. Doxycycline is associated with a higher relapse rate and requires a longer duration of therapy. (Murray 2022)
• (Macrolides such as azithromycin are not effective.)

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Coxiella burnetii (Q fever)

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diagnostic clues

• 🔍 Exposure to animals is a key clue. Note that the incubation is 7-40 days, so exposure may be remote.
• 🔍 Lack of upper respiratory symptoms (unlike most atypical pneumonias).
• 🔍 Radiologically, may appear as a lobar pneumonia, but lymphadenopathy can be a useful clue. Splenomegaly may also be a useful clue (seen in psittacosis or Q-fever). (28159178)

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epidemiology

• Q-fever is among the rarest causes of community-acquired pneumonia. (33835878)
• It is vectored by a variety of animals, most often cattle, sheep, and goats (also cats, dogs, rabbits). 🐐 Q-fever is transmitted via inhalation of aerosols formed from placental derivatives, feces, or urine. (32629489) It may survive in the environment (e.g., manure dust) for months to years.
• At-risk population includes farmers, veterinarians, and slaughterhouse workers.
• The infective dose is very small, so minimal animal contact is required (one outbreak occurred after infected sheep passed through a village).
• Distribution is seasonal, mostly in the spring and summer. (32629489)
• Epidemiology within the United States is shown below. (CDC) Q-fever is also distributed worldwide, with some areas of hyperendemicity (e.g., French Guiana).

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clinical presentation

• Incubation lasts 7-40 days, followed by insidious onset. (27276986)
• Constitutional symptoms include fever, severe headache, chills/sweats, arthralgias, and myalgias.
• Pulmonary:
  • Cough in about half of patients.
  • Chest pain.
• Disease severity: (31279382)
  • ~60% of infected people are asymptomatic.
  • ~38% have mild to moderate disease.
  • <2% present with severe disease.

pulmonary complications

• Overall, pneumonia is usually mild and with low mortality. However, severe pneumonia may occur, including rapid progression to ARDS. (24813862)
• Secondary organizing pneumonia can occur. (31279382)

multisystem involvement

• Neurologic:
  • Meningoencephalitis, with severe headache and/or photophobia.
  • Guillain-Barre syndrome may occur.
• Cardiovascular: pericarditis, myocarditis, or endocarditis can occur.
• Dermatologic signs are rare (compared to other atypical pneumonias):(Fishman 2023) 
  • Nonspecific maculopapular or vesicular rash in ~5% of patients.
  • Erythema nodosum.
  • Conjunctivitis.
• GI: nausea/vomiting, abdominal pain, diarrhea, hepatitis, pancreatitis.
• Hematologic: splenomegaly, splenic rupture. (24813862)

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radiology

• (1) Lobar-type pneumonia:
  • Dense, homogeneous segmental or lobar consolidation may occur (similar to pneumococcal pneumonia).
  • Multiple nodular opacities may occur, sometimes with a surrounding halo. (Murray 2022) These may simulate the appearance of tricuspid endocarditis with septic pulmonary emboli.
• (2) Mediastinal lymphadenopathy may be seen (may mimic lymphoma).
• (3) Pleural effusion may occur in up to a third of patients. (Walker 2019)

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laboratory tests

general labs

• Thrombocytopenia occurs in ~25% of patients.
• WBC count is elevated in ~25% of patients, but less often than with other pneumonias. (Fishman 2023)
• CRP is markedly elevated. (Murray 2022)
• Autoimmune markers have been detected (e.g., antinuclear antibodies, antiphospholipid antibodies, antineutrophil cytoplasmic antibodies). (32629489)
• Hepatitis is common, seen in up to 85% of patients. (32629489)

serology

• Serology remains the most commonly used test for specific identification.
• Seroconversion usually occurs by 1-2 weeks after onset of symptoms. (Fishman 2023)

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treatment

• Antibiotic therapy:
  • Doxycycline is recommended therapy for 14-21 days (given variable resistance to macrolides and reported resistance to fluoroquinolones). (24626238; 24813862, 32629489) 
  • In pregnancy, trimethoprim-sulfamethoxazole may be a treatment option. (32629489)
• If imaging is suggestive of secondary organizing pneumonia, the addition of steroid may be considered. (31279382)
• Mortality is rare, but 1-2% of patients may develop chronic infection (e.g., endocarditis or vascular graft infection).

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leptospirosis

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basics

• Leptospira is a zoonotic gram-negative aerobic spirochete.
• The disease evolves in several stages. The immunologic phase (Weil disease) is most severe and this is most likely to lead to hospitalization and/or ICU admission, so this is the focus of the discussion below.

epidemiology

• Leptospirosis is found worldwide, but predominantly in tropical and subtropical areas.
• Leptospira persist in the renal tubules of animals, with excretion in the urine. Organisms may remain viable in stagnant water for several weeks, most often being transmitted to humans via contaminated water. However, transmission can also occur via direct animal contact, or contact with contaminated soil.
• Rodents are the primary vector, but other animals can also be infected (e.g., dogs, cattle, pigs).
• High-risk groups may include:
  • Veterinarians.
  • Farmers, slaughterhouse workers.
  • Construction workers.
  • Contact with rats within cities, sewage workers.

clinical evolution

• Most patients have mild illness, but severe disease occurs in ~10% of patients.
• (1) Incubation usually lasts 1-2 weeks (with a range of ~2-20 days). (35078790)
• (2) Leptospiremic phase, aka acute phase:
  • Usually this presents with abrupt onset of rigors, fever, myalgias, and headache. (29129539) Myalgia may be severe, potentially mimicking a surgical abdomen (due to abdominal tenderness) or meningitis (due to paraspinal muscle involvement). (35078790)
  • Conjunctival suffusion is seen in most patients (redness without exudate), often with subconjunctival hemorrhages.
  • Nonproductive cough, and/or GI symptoms (nausea/vomiting, diarrhea) may occur.
  • Symptoms often last ~3-9 days followed by spontaneous resolution, prior to transition into the immunologic phase. However, the leptospiremic phase can overlap with the immunologic phase, without any definitive improvement in between. (35078790) 
• (3) Immunologic phase, aka Weil disease (occurs ~4-30 days after the initial phase), which may cause multi-organ failure as discussed further below.
  • This is the phase of disease that will generally be seen among patients admitted to the hospital or ICU.

clinical features of the immunological phase (Weil disease)

• Renal failure.
  • Leptospirosis may inhibit the Na-K-Cl cotransporter, thereby inducing diuresis.
  • Renal failure may result from a combination of:
    • Volume depletion.
    • Interstitial nephritis.
    • Possibly, immune complex-mediated glomerulonephritis.
    • Rhabdomyolysis. (29129539, 31898795)
• Gastrointestinal involvement:
  • Jaundice and hepatosplenomegaly are common.
  • Pancreatitis can occur.
• Cardiac involvement:
  • Cardiac dysrhythmias may occur.
  • Interstitial myocarditis may cause cardiac failure.
• Respiratory failure:
  • Respiratory failure can occur (including ARDS).
  • Diffuse alveolar hemorrhage may occur.
• CNS involvement:
  • Meningoencephalitis with delirium/coma may occur.
  • Aseptic meningitis with meningismus may occur.
  • Diffuse cerebral edema may be seen on CT scan in about a quarter of patients. (29129539)
  • Acute disseminated encephalomyelitis, transverse myelitis, hydrocephalus, intracranial bleeding and thrombosis, and Guillain-Barre syndrome can occur. (29129539; 35078790)
• Conjunctival injection (with or without hemorrhage); ocular pain.
• Pharyngitis.
• Lymphadenopathy.
• Skin rash may occur.
• Myalgia, muscle tenderness and rigidity. (29129539)

laboratory tests (immunological phase)

• Blood count:
  • Leukocytosis usually occurs, with a left shift (e.g., bandemia).
  • Atypical lymphocytosis may occur. (17051497) 
  • Thrombocytopenia usually occurs (even in the absence of DIC). (37525113)
  • Pancytopenia can occur.
• Liver function tests:
  • Bilirubin may increase to 80 mg/dL, but usually remains ~30-40 mg/dL.
  • Transaminase levels are often not substantially elevated (e.g., <200 IU/L).
• Urinalysis typically shows proteinuria and pyuria (due to interstitial nephritis), granular casts, and occasionally microscopic hematuria. (29129539)
• Coagulation studies: DIC may occur. (35078790)
• Creatinine kinase: rhabdomyolysis may occur.
• CSF may show lymphocytic pleocytosis (mean 50 cells/uL) and elevated protein (115 +/- 67 mg/dL). (29129539)
• Leptospira IgM:
  • This seems to be the primary test that is clinically available.
  • Serology may be negative in the initial disease phases, but is often positive >5 days after onset of symptoms. (29129539)
  • A single titer of >1:200 but less than 1:800 is suggestive of leptospirosis. (28564558)
  • A single titer >1:800 confirms current or recent infection. (29129539)
  • Increase in titers during convalescence is confirmatory (but obviously doesn't provide a prompt diagnosis).

differential diagnosis

• Differential diagnosis is broad, including such disorders as:
  • Dengue fever, malaria.
  • Influenza.
  • Hantavirus.
  • Anaplasmosis or ehrlichiosis.
  • Meningococcemia.
  • TTP (thrombotic thrombocytopenic purpura).
  • HLH (hemophagocytic lymphohistiocytosis) due to other etiologies.
• Conjunctival suffusion may be one of the most reliable distinguishing features, since it rarely occurs with other infectious illnesses (other than viral hemorrhagic fevers). (29129539) However, numerous other causes of respiratory failure with conjunctival involvement exist, including: 
  • Mycoplasma.
  • HSV.
  • COVID.
  • Streptococcus pneumoniae (pneumococcal conjunctivitis).
  • Lupus.
  • GPA (granulomatosis with polyangiitis).
  • Sarcoidosis.

treatment

• Supportive care:
  • Discontinue any potentially nephrotoxic or hepatotoxic medications. (35078790)
  • Dialysis may be required.
  • Mechanical ventilation may be needed for respiratory failure.
  • Hemodynamic support may be required.
  • If rhabdomyolysis occurs, it should be treated. 📖
• Antibiotic therapy:
  • By the time most patients present to the hospital (and especially the ICU), the organism is already being cleared by the immune system. Consequently, the impact of antibiotic therapy is unclear. Nonetheless, antibiotics should be administered as soon as possible. (29129539)
  • Mild leptospirosis may be treated with: doxycycline, ampicillin, amoxicillin, or azithromycin.
  • Moderate-to-severe leptospirosis may be treated with penicillin G, ampicillin, or ceftriaxone 1 gram BID. Second-line options include doxycycline or azithromycin. (35078790)
• Steroid therapy:
  • There is little high-quality data, but some evidence supports the use of moderate doses of steroid among patients with more severe illness (e.g., equivalent to 1 mg/kg/day prednisone). (25763200) 
  • Administration of steroid prior to, or simultaneous with, antibiotic therapy might theoretically reduce the severity of the Jarisch-Herxheimer reaction (clinical deterioration due to bacteriolysis following antibiotic therapy).
  • Rarely, leptospirosis may trigger hemophagocytic lymphohistiocytosis (HLH), which could require additional therapies. (34336315)

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