Atypical Pneumonia

Pneumonia caused by organisms that do not stain on Gram stain and are not killed by beta lactam antibiotics: Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, Chlamydophila psittaci (psittacosis), Coxiella burnetii (Q fever) and Francisella tularensis. Respiratory viruses give a similar picture. Together they cause about 10 to 40% of community acquired pneumonia.

• Mycoplasma causes epidemics every 3 to 7 years, mostly in school age children and young adults. Chlamydophila pneumoniae affects older adults. Legionella (about 2 to 9% of community acquired pneumonia) is acquired from contaminated water systems (cooling towers, showers, spas, hospital pipes) and carries mortality of about 5 to 15% (higher in hospital acquired disease). Psittacosis follows exposure to birds. Q fever follows contact with livestock and birth products, and is relevant in pastoralist communities in East Africa.

• Gradual onset over days, with headache, myalgia, sore throat, dry cough, low grade fever, and chest signs milder than the X-ray suggests. Legionella is more severe: high fever, relative bradycardia, diarrhoea, confusion, hyponatraemia, raised liver enzymes and creatine kinase, and acute kidney injury.
• Extrapulmonary features: haemolytic anaemia with cold agglutinins, rash (erythema multiforme, Stevens-Johnson syndrome), bullous myringitis, hepatitis, pericarditis and myocarditis, neurological syndromes (encephalitis, Guillain-Barre syndrome), splenomegaly (psittacosis, Q fever), culture negative endocarditis (Q fever).
• Differential diagnosis: pneumococcal pneumonia, viral pneumonia (influenza, SARS-CoV-2), tuberculosis, Pneumocystis pneumonia, pulmonary embolism, sarcoidosis, organising pneumonia, vasculitis, fungal infection.
• Complications: respiratory failure and ARDS, pleural effusion, acute kidney injury, rhabdomyolysis, haemolysis, myocarditis, meningoencephalitis, chronic Q fever (endocarditis, vascular infection), and post-infectious bronchial hyperreactivity.

• Chest X-ray: patchy or interstitial infiltrates, often unilateral lower lobe; lobar consolidation in Legionella; effusion in about 20% with Mycoplasma. Findings are often worse than the clinical signs.
• Blood tests: full blood count (white cell count usually normal), sodium (low in Legionella), liver function, creatine kinase, creatinine, CRP, cold agglutinin titre (1:64 or more supports Mycoplasma), direct antiglobulin test when haemolysis is suspected, HIV test.
• Specific tests:
  • Legionella urinary antigen (detects serogroup 1, sensitivity about 70 to 80%) and PCR or culture of a lower respiratory sample on buffered charcoal yeast extract agar.
  • Mycoplasma PCR on throat swab, nasopharyngeal swab or sputum, with serology (IgM or a four fold rise in IgG) as back up.
  • Chlamydophila PCR on respiratory samples; psittacosis PCR and paired serology.
  • Q fever: phase II IgG and IgM serology, and PCR on blood in the first 2 weeks.
  • Respiratory viral PCR panel.
• Microbiology is also needed to exclude tuberculosis (Xpert MTB/RIF) when cough lasts more than 2 weeks or in HIV.

• Treat with agents that act inside cells.
• Outpatient or non-severe:
  • Azithromycin 500 mg on day 1 then 250 mg daily for 4 days (or 500 mg daily for 3 days); or clarithromycin 500 mg twice daily for 7 to 14 days; or doxycycline 200 mg on day 1 then 100 mg twice daily for 7 to 14 days.
  • Levofloxacin 750 mg daily (or 500 mg twice daily) for 5 to 7 days, or moxifloxacin 400 mg daily, as alternatives when macrolides and tetracyclines cannot be used.
• Severe disease or Legionella:
  • Levofloxacin 750 mg IV or orally daily or azithromycin 500 mg IV or orally daily for 7 to 14 days; 14 to 21 days in immunosuppressed or severe cases. Combination of a fluoroquinolone with azithromycin is used in the most severe cases (evidence is limited).
• Psittacosis: doxycycline 100 mg twice daily for 10 to 14 days (21 days if severe or relapsing); IV doxycycline 100 mg twice daily when unwell.
• Q fever, acute: doxycycline 100 mg twice daily for 14 days. Chronic Q fever with endocarditis needs doxycycline 100 mg twice daily plus hydroxychloroquine 200 mg three times daily for at least 18 months (native valve) or 24 months (prosthetic valve), with serology every 3 months and valve surgery in most.
• Tularaemia: gentamicin 5 mg/kg IV daily for 10 days, or doxycycline 100 mg twice daily for 14 to 21 days in mild disease.
• Macrolide resistant Mycoplasma (rates vary widely; high in East Asia, uncertain in Africa): if fever persists after 48 to 72 hours, switch to doxycycline or a fluoroquinolone.
• Supportive care: oxygen, fluids, paracetamol 1 g four times daily, thromboprophylaxis with enoxaparin 40 mg SC daily when admitted, and dialysis for acute kidney injury. Corticosteroids (methylprednisolone 1 to 2 mg/kg/day for 3 to 5 days) are used only for refractory Mycoplasma with extrapulmonary disease; evidence is limited.
• Legionella source control: report cases, disinfect the implicated water system, and investigate clusters.
• Special groups:
  • Children: azithromycin 10 mg/kg once on day 1 then 5 mg/kg daily for 4 days (maximum 500 mg then 250 mg), or clarithromycin 15 mg/kg/day in 2 divided doses for 7 to 14 days; doxycycline 2.2 mg/kg twice daily (maximum 100 mg) for 7 to 14 days is acceptable; use fluoroquinolones only when no alternative exists.
  • Pregnancy: azithromycin or erythromycin 500 mg four times daily; avoid doxycycline and fluoroquinolones. For Q fever in pregnancy, use co-trimoxazole 960 mg twice daily with folic acid 5 mg daily (avoid near term), with specialist input; evidence is limited.
  • Renal impairment: adjust levofloxacin and avoid clarithromycin accumulation; check creatine kinase and creatinine daily in Legionella.
  • QT prolongation: avoid macrolide and fluoroquinolone combinations, and check an ECG.
  • HIV and immunosuppression: longer courses (Legionella 14 to 21 days), and rule out tuberculosis and Pneumocystis pneumonia.
• Red flags: respiratory failure, confusion, hyponatraemia with sodium less than 130 mmol/L, creatinine rise, haemolysis, valvular murmur or fever after Q fever.
• Follow up: review at 48 to 72 hours and 6 weeks; chest X-ray at 6 weeks if symptoms persist; serology every 3 months for Q fever with valve disease or immunosuppression; echocardiography for Q fever in patients with valvulopathy.