Recurrent infections

Recurrent infections are repeated infections beyond the number or severity expected for age and exposure. They may also recur at the same site, involve unusual organisms, or fail to clear with appropriate treatment.

In adults, examples include:

• 2 or more serious bacterial infections in 1 year
• 4 or more antibiotic treated infections in 1 year
• recurrent pneumonia (2 or more in 1 year)
• recurrent sinusitis (4 or more in a year)
• recurrent urinary tract infection (2 in 6 months or 3 in 12 months)
• recurrent skin abscesses
• recurrent genital herpes or candidiasis
• infections with opportunistic organisms

Clinical relevance. Most recurrent infection has a local anatomical, behavioural, exposure or host cause (obstruction, foreign body, chronic disease, diabetes, drug exposure). A smaller number have an immune defect (primary or secondary immunodeficiency). The pattern of organism and site points to the defect. HIV and tuberculosis are the leading causes of acquired immunodeficiency in Africa.

Classification.

• Local or anatomical: obstruction (stones, tumour, stricture), abnormal drainage (sinus ostia, eustachian tube, bronchiectasis), foreign bodies, fistula, structural lung disease, vesicoureteric reflux, retained products, dental disease, devices (catheters, shunts, prostheses), skin barrier disruption.
• Exposure and behaviour: household and occupational exposure, school or day care, smoking, sexual behaviour, injecting drug use, poor hygiene or sanitation, malnutrition.
• Host systemic: diabetes mellitus, malnutrition, alcohol use disorder, chronic kidney disease, cirrhosis, malignancy, sickle cell disease, hyposplenism, allergies and atopy.
• Secondary immunodeficiency: HIV infection, immunosuppressive and chemotherapy drugs, corticosteroids, biological agents, haematological malignancy, protein losing states, splenectomy.
• Primary immunodeficiency: antibody deficiency (common variable immunodeficiency, selective IgA deficiency, X linked agammaglobulinaemia), complement deficiency, phagocyte defects (chronic granulomatous disease), T cell and combined defects, innate immune defects.

Warning signs of immunodeficiency.

• Two or more deep seated infections
• infections at unusual sites
• unusual or opportunistic organisms
• failure to clear with usual treatment
• need for intravenous antibiotics
• persistent thrush or warts
• family history of immunodeficiency or early death
• autoimmunity with infection
• poor response to vaccination
• chronic diarrhoea
• failure to thrive

History.

• Site, organism (if known), frequency, severity, duration, response to treatment, need for hospital admission and intravenous drugs, complications (empyema, bronchiectasis, meningitis, sepsis).
• Pattern: respiratory (sinusitis, otitis, pneumonia, bronchitis), urinary, skin and soft tissue, gastrointestinal, genital, central nervous system, bone and joint, deep abscess.
• Organisms: encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) suggest antibody, complement or spleen defects. Neisseria suggests complement deficiency.
• Staphylococcus aureus, Aspergillus, Nocardia, Candida and Burkholderia suggest phagocyte defects.
• Viruses, Pneumocystis, cytomegalovirus, mycobacteria and fungi suggest T cell defects.
• Risk for HIV (sexual history, blood exposure), tuberculosis contact, diabetes symptoms, drug and alcohol use, smoking, malnutrition, weight loss.
• Medications: corticosteroids, methotrexate, azathioprine, mycophenolate, cyclophosphamide, rituximab, tumour necrosis factor inhibitors, chemotherapy, antiepileptics, inhaled steroid dose, proton pump inhibitors, antibiotics.
• Surgical history: splenectomy, transplant, implants, shunts, catheters.
• Early childhood: infections, infant deaths, vaccination response, complication after live vaccines.
• Family history of immunodeficiency, autoimmune disease, early death, consanguinity.
• Associated features: diarrhoea, weight loss, rash, eczema, autoimmune cytopenia, arthritis, lymphoma, granulomas, sinopulmonary disease.
• Exposures: occupational, travel, animals, water, children at home.

Examination.

• Growth, weight, body mass index, wasting, pallor, jaundice.
• Skin: eczema, scars, abscesses, warts, molluscum, candidiasis, vasculitis, telangiectasia, albinism.
• Mouth: thrush, ulcers, gingivitis, dental caries, leukoplakia (oral hairy). Ears, nose, throat: chronic discharge, perforation, nasal polyps.
• Lymph nodes (absent tonsils or nodes suggest antibody deficiency; massive nodes suggest lymphoproliferation), spleen, liver.
• Chest: crackles, bronchiectasis, clubbing, hyperinflation. Heart: murmurs and endocarditis stigmata.
• Joints, nails, eyes, genitalia, rectal region and perianal region (abscess, fistula).
• Foreign bodies, devices, catheters, wound sites.

Red flags.

• Life threatening infection (sepsis, meningitis, necrotising infection) or intensive care admission.
• Opportunistic infection (Pneumocystis pneumonia, cryptococcosis, cytomegalovirus, disseminated mycobacterial infection, invasive aspergillosis, Kaposi sarcoma).
• Persistent oral candidiasis, severe herpes zoster under age 50, recurrent zoster, chronic diarrhoea, weight loss.
• Recurrent pneumonia in the same lobe (obstruction, bronchiectasis, foreign body).
• Recurrent meningococcal or pneumococcal infection (complement or splenic defect).
• Deep abscesses in liver, lung, skin or lymph nodes (phagocyte defects).
• Unexplained cytopenia, hypogammaglobulinaemia, lymphoma.
• Young adults with infections and autoimmunity, family history of immunodeficiency.
• Pregnancy with HIV.

Local and anatomical.

• Bronchiectasis (post infective, cystic fibrosis, ciliary dyskinesia, allergic bronchopulmonary aspergillosis)
• endobronchial obstruction (tumour, foreign body, tuberculous stricture)
• chronic rhinosinusitis with polyps or septal deviation
• eustachian tube dysfunction
• urinary stones
• outflow obstruction (prostate, stricture)
• vesicoureteric reflux
• neurogenic bladder
• urinary catheter
• chronic osteomyelitis with retained hardware
• recurrent skin abscess (carriage of Staphylococcus aureus, hidradenitis suppurativa, pilonidal disease)
• dental infection
• fistula
• gastro-oesophageal reflux with recurrent aspiration
• swallowing disorder

Host factors and chronic disease. Diabetes mellitus, malnutrition, obesity, chronic kidney disease and nephrotic syndrome, cirrhosis, alcohol use disorder, smoking, chronic obstructive pulmonary disease, asthma, sickle cell disease, thalassaemia, hyposplenism or asplenia, protein losing enteropathy, burns, eczema or skin barrier disorder, neutropenia.

Secondary immunodeficiency.

• HIV infection
• medicines: corticosteroids, cytotoxic and immunosuppressive drugs, rituximab, anti tumour necrosis factor drugs, and antiepileptics such as phenytoin and carbamazepine causing IgA and IgG deficiency
• haematological malignancy (chronic lymphocytic leukaemia, myeloma, lymphoma)
• solid cancer, radiation, transplant
• tuberculosis, malaria, schistosomiasis and other infections that impair immunity
• ageing, pregnancy

Primary immunodeficiency.

• Common variable immunodeficiency
• selective IgA deficiency
• IgG subclass deficiency
• specific antibody deficiency
• X linked agammaglobulinaemia
• hyper IgM syndrome
• severe combined immunodeficiency (in infants)
• complement deficiencies (C3, terminal complement, C1 esterase inhibitor)
• phagocyte disorders (chronic granulomatous disease, leucocyte adhesion deficiency, Chediak-Higashi syndrome, cyclic neutropenia)
• hyper IgE syndrome
• chronic mucocutaneous candidiasis
• interferon gamma and interleukin 12 signalling defects
• DiGeorge syndrome
• Wiskott-Aldrich syndrome
• ataxia telangiectasia
• innate immune defects (Toll-like receptor signalling)

Mimics. Allergic disease (allergic rhinitis, asthma) that mimics infection, chronic cough from reflux or upper airway cough syndrome, recurrent viral infections in healthy people with heavy exposure, chronic urinary symptoms without infection (interstitial cystitis, urethral syndrome), non infective inflammation (vasculitis, autoimmune disease, periodic fever).

1. Document the infections: dates, sites, cultures, imaging, treatments and outcomes. Decide whether local, exposure or host factors explain the pattern before looking for immunodeficiency.
2. First line tests: full blood count with differential (neutrophil, lymphocyte, eosinophil, platelet counts; lymphopenia under 1.0 x 10^9/L), ESR and C reactive protein, urea, creatinine and electrolytes, liver function tests, glucose and HbA1c.
3. Also: urinalysis and urine culture, HIV test with consent, thyroid stimulating hormone, chest radiograph, and nutritional assessment.
4. Local factors: imaging directed to the site (CT sinuses, high resolution CT chest, renal ultrasound, cystoscopy, MRI for osteomyelitis), bronchoscopy for obstruction, sputum culture including acid fast bacilli and fungi, swallowing assessment, and Staphylococcus aureus nasal swab.
5. Immune evaluation if infections are recurrent, severe, unusual or with warning signs:

• Immunoglobulins IgG, IgA, IgM, and IgE; serum protein electrophoresis with immunofixation (to exclude myeloma).
• Specific antibody response to vaccines (pneumococcal polysaccharide, tetanus, Haemophilus influenzae type b); low titres or failure to respond after vaccine suggests specific antibody deficiency.
• Lymphocyte subsets (CD3, CD4, CD8, CD19, CD16/56), and CD4 count.
• Complement: C3, C4, CH50 (total haemolytic complement) and AH50 (alternative complement activity).
• Neutrophil function: nitroblue tetrazolium or dihydrorhodamine flow cytometry test for chronic granulomatous disease.
• HIV viral load, HIV antibody and antigen.
• Genetic testing and referral to an immunologist when a primary defect is likely.

1. Secondary causes: HIV, tuberculosis (interferon gamma release assay, sputum), hepatitis B and C, syphilis, HTLV-1, serum protein electrophoresis, free light chains, urine protein, albumin, lymphocytes, peripheral film, bone marrow, CT for lymphoma, and medicine review.
2. Spleen function: Howell-Jolly bodies on film, ultrasound or CT.
3. Cystic fibrosis and ciliary studies (sweat chloride, nasal nitric oxide, ciliary biopsy) for suspected bronchiectasis.
4. Allergy testing (skin prick, specific IgE, Aspergillus IgE, IgG precipitins) for suspected allergic bronchopulmonary aspergillosis or atopy.

Limits. Immunoglobulin levels vary with age and acute illness. Specific antibody tests should be interpreted by an immunologist. Normal screening does not exclude cellular or innate defects. Low IgG can result from drugs, protein loss or lymphoproliferative disease.

Treat the acute infection with culture directed antibiotics, drainage of collections and removal of devices.

Cause directed treatment.

• Anatomical causes: relieve obstruction, remove foreign body or stone, drain collections, treat structural disease (sinus surgery, bronchoscopic removal, lithotripsy, surgical repair).
• Bronchiectasis: airway clearance physiotherapy, hypertonic saline 7% nebulised twice daily, and vaccination.
• For frequent exacerbations of bronchiectasis, give long term azithromycin 250 mg orally daily or 500 mg three times weekly. Check ECG for QT, and exclude non tuberculous mycobacteria.
• Recurrent urinary tract infection (women): behavioural measures (fluid intake 2 litres daily, post coital voiding), vaginal oestrogen in postmenopausal women, methenamine hippurate 1 g twice daily, and cranberry products.
• Antibiotic prophylaxis for recurrent urinary tract infection: nitrofurantoin 50 to 100 mg at night or trimethoprim 100 mg at night for 6 months, or a single post coital dose.
• Treat acute urinary episodes with nitrofurantoin 100 mg modified release twice daily for 3 days (avoid if eGFR under 45) or pivmecillinam 400 mg three times daily for 3 days.
• Recurrent skin abscess: decolonise Staphylococcus aureus with mupirocin 2% nasal ointment twice daily for 5 days and chlorhexidine 4% body wash daily for 5 to 7 days. Treat household contacts and reinforce hygiene measures.
• Recurrent sinusitis and otitis: nasal saline irrigation, intranasal corticosteroids (mometasone 2 sprays each nostril daily), allergy management, and surgery for structural disease.
• Diabetes mellitus: optimise glycaemic control (HbA1c target about 48 to 58 mmol/mol, individualised).
• Malnutrition and alcohol use disorder: nutritional support, thiamine 100 mg daily, and addiction treatment.
• HIV infection: start antiretroviral therapy without delay (tenofovir 300 mg, lamivudine 300 mg and dolutegravir 50 mg once daily). Add vaccination.
• HIV prophylaxis: cotrimoxazole 960 mg daily when CD4 is under 350 cells/microlitre, tuberculosis screening, and isoniazid preventive therapy 300 mg daily with pyridoxine 25 mg daily.
• Medicine related immune suppression: reduce or change the drug if possible. Give prophylaxis (cotrimoxazole 480 mg daily or 960 mg three times weekly for Pneumocystis in prolonged high dose steroids or other agents).
• Asplenia and hyposplenism: vaccines (pneumococcal conjugate then polysaccharide, Haemophilus influenzae type b, meningococcal ACWY and B, annual influenza).
• Also give lifelong penicillin V 250 mg twice daily (or erythromycin 250 mg twice daily if allergic) and a rescue antibiotic plan with early medical review for fever.
• Primary antibody deficiency, specialist directed: immunoglobulin replacement (intravenous 0.4 to 0.6 g/kg every 3 to 4 weeks, or subcutaneous 0.1 to 0.15 g/kg weekly, aiming for trough IgG over 6 g/L).
• Add prophylactic antibiotics (azithromycin 250 mg three times weekly or co-trimoxazole 480 mg daily) and airway clearance. Monitor for bronchiectasis, autoimmunity and lymphoma.
• Phagocyte defects: itraconazole 200 mg daily and co-trimoxazole 960 mg twice daily prophylaxis in chronic granulomatous disease, interferon gamma 50 micrograms/m2 three times weekly, and bone marrow transplantation.
• Complement deficiency: vaccination and antibiotic prophylaxis.
• Allergic bronchopulmonary aspergillosis: prednisolone 0.5 mg/kg daily for 2 weeks then taper over months, with itraconazole 200 mg twice daily.
• Vaccination: influenza yearly, pneumococcal, COVID-19, hepatitis B, and others as indicated. Avoid live vaccines in significant immunosuppression.
• Neutropenia: urgent assessment, granulocyte colony stimulating factor, and treat fever as an emergency (piperacillin-tazobactam 4.5 g intravenously every 6 hours).

General measures. Smoking cessation, hand hygiene, nutrition, dental care, safe water, vaccination, and treatment of atopy.

Monitoring. Review infection frequency, immunoglobulin trough levels and organ damage every 3 to 6 months, CD4 and viral load for HIV, and repeat high resolution CT for bronchiectasis as needed.

Referral and escalation. Immunology for suspected primary or complex secondary immunodeficiency. Infectious diseases or HIV services. Respiratory, urology, ENT, nephrology, diabetes, haematology as indicated. Genetics for family history.

Admission. Sepsis, severe or opportunistic infection, neutropenic fever, meningitis, deep abscess needing drainage, and failure of oral therapy.

Safety netting. Return urgently for fever with rigors, breathlessness, confusion, stiff neck, rash, severe pain, vomiting, or failure to respond to treatment.

Special groups.

• Children: evaluate growth and vaccine response. Severe combined immunodeficiency is an emergency (infant with persistent thrush, diarrhoea, failure to thrive, lymphopenia). Avoid live vaccines pending evaluation.
• Pregnancy: treat HIV for mother and baby, avoid certain drugs, and screen for urinary tract infection.
• Older adults: diabetes, malignancy, drugs and malnutrition are common causes.
• Endemic regions: HIV, tuberculosis, malnutrition, sickle cell disease, malaria and schistosomiasis are leading contributors.