Susceptibility to Infections in Adults

Essentials

• Increased susceptibility to infections is more often due to patient characteristics (age, damaged skin or mucous membranes, structural characteristics of the lungs or maxillary sinuses, sufficient vasculature), diseases, prevalence of infections (day care), or habits (smoking, intoxicants) than to immunodeficiency.
• HIV infection is the most common disease causing immunodeficiency worldwide. All patients with suspected increased susceptibility to infections should have an HIV test.
• Increased susceptibility to infections may be due to genetically defined (primary) or secondary immunodeficiency.
• Hospital treatment, medication (glucocorticoids, anticancer or antirheumatic drugs), foreign bodies (cannulas, prostheses) and procedures may increase the susceptibility to infections.
• Significant susceptibility to infections threatens the patient's health and, untreated, leads to premature death and/or sustained damage to target organs (e.g. the lungs).
• Significant susceptibility to infections requiring immunological studies can normally be identified by careful history taking.
• An explanation should be sought for the increased susceptibility to infections, and in cases of unclear aetiology, based on the history, referral to an outpatient clinic specializing in such cases should be considered.

Normal frequency of infections

• The following can be considered to be within the limits of normal and ordinary frequency of infections:
  • In adults 2 to 4 or, in the case of increased exposure, up to 5 to 8 viral upper respiratory tract infections per year
  • Recurrent prolonged upper respiratory tract infections, maxillary sinusitis and bronchitis beginning with the clinical picture of a viral disease and without diagnosed invasive bacterial infection - particularly in connection with susceptibility to inflammation, for example, in smokers with COPD or in patients with asthma, atopy, nasal polyposis or depression
  • Individual episodes of infection, even bacterial, recurring infrequently and responding well to correctly chosen antimicrobial treatment.
• In recurrent maxillary sinusites without other findings suggestive of immunodeficiency no further examinations of the immune system are normally indicated. An otologist should assess the need for treating any structural obstruction.
  • Patients with allergy, COPD or asthma may have more frequent clinical infections with more severe symptoms.
• Note that
  • patients with a functional immunological system usually recover well from infectious diseases without requiring longer courses of antimicrobial drugs
  • uncomplicated recurrent urinary tract infections in women are usually not due to an immunological disorder
  • immunodeficiency is rarely diagnosed in patients with recurrent bacterial skin infections (erysipelas, superficial abscesses) without deep abscesses or other more invasive infections.
• If microbiological samples during inflammatory episodes do not regularly suggest a microbial disease or an autoimmune disease, a specialized clinic can be consulted also when an autoinflammatory disease is suspected.

History

• Screen for susceptibility to infections based on patient history.
• The patient should be asked about any significant infectious diseases, methods used to diagnose such diseases, and the findings, and these should be recorded chronologically from childhood to the present day.
• Any complications, therapeutic response and recovery schedule also constitute essential information.
• Note that a single episode of pneumonia, for instance, in a patient with immunodeficiency may be completely identical to pneumonia in a patient with a perfectly healthy immune system; only recurrent infections identified by careful history taking can suggest immunodeficiency.

Suspicion of abnormal susceptibility to infection

• Abnormal susceptibility to infection should be suspected if
  • there is or has been primary immunodeficiency in the family
  • the patient has had at least 3 episodes of pneumonia requiring hospital treatment or verified by x-ray, particularly migratory pneumonia (table T1, picture )
  • the patient has had more than 4 respiratory tract infections per year that have required antimicrobial treatment (see Differential diagnosis below) and that are not explained by e.g. smoking or an underlying disease, such as nasal polyposis (see above).
  • the patient has had 2 severe bacterial infections (meningitis, sepsis, osteomyelitis) that are not explained by, for example, diabetes or illegal drug use
  • the patient has had 2 severe invasive viral infections (e.g. prolonged viraemia or encephalitis)
  • the cause or place of infection is or has been unusual
  • the patient's severe infection is or has been caused by microbes usually only seen in people with immunodeficiency
  • the response to antimicrobial drugs chosen on well justified grounds is or has been repeatedly poor
  • the patient has or has had a susceptibility to infections as described above with chronic diarrhoea and/or a cluster of relevant autoimmune diseases (table T2, picture ).
• In addition to susceptibility to infection, the following reasons, among others, have typically lead to investigations in persons with antibody deficiencies.
  • fluctuating increase in liver test results
  • inflammatory bowel diseases
  • granulomas, atypical sarcoidosis with regard to its type or treatment response
  • enlargement of lymph node(s)
  • severe and recurring aphthous mucosal lesions
  • enlargement of the spleen or hypersplenism
• In the region of Helsinki in Finland, hypogammaglobulinaemia is found as the underlying cause of increased liver test results over 20 times more often than copper storage disease (Wilson's disease).

The most common immunodeficiencies in adults

• Secondary immunodeficiency is distinctly more common than primary immunodeficiency.
  • It is particularly important to examine the possibility of HIV infection and consider the need for supportive treatment in patients who have received significant treatment with immunomodulators.
• On the population level, primary immunodeficiency is rare (approx. 1.2:10 000). Before diagnosis and treatment, the recurrent need for treatment often makes these patients large-scale consumers of health care services.
• Recurrent pneumonia or sepsis, or severe purulent respiratory infections diagnosed by bacterial culture and appearing for the first time in adulthood may suggest adult-onset antibody deficiency.
• Of patients with primary immunodeficiency (more than 200 different types), about 70% suffer from antibody deficiency.
• Of immunodeficiencies diagnosed in adults, about 90% are antibody deficiencies; about 90% of antibody deficiencies do not manifest until adulthood.
• The diagnosis and treatment of primary immunodeficiencies in adults is concentrated in central and university hospital departments of infectious diseases.

Primary investigations in primary health care

• HIVAgAb, complete blood count and plasma or serum IgG, IgA, IgM, IgE
• If reduced antibody levels are detected, the patient should be informed about the need for further investigations.
• If the results are normal but the patient still has recurrent invasive infections (such as migratory pneumonia, sepsis, meningitis) or highly exceptional causative pathogens, an infectious disease specialist should probably be consulted.
• If the main problem is recurrent maxillary sinus Acute Maxillary Sinusitis and/or bronchial symptoms Acute Bronchitis, further treatment and examinations should be planned in consultation with a specialist in pulmonology or otology, as necessary.
• In recurrent urinary tract infections Urinary Tract Infections or recurrent erysipelas Erysipelas, the normal therapeutic practice should be followed.
• If appropriate, referral to a specialist department to determine whether the low level of antibodies is genetic or has other causes (e.g. medication, haematological disease, loss in faeces or in urine)

Differential diagnosis

• Most patients with recurrent respiratory tract infections have no significant immunodeficiency.
• Patients with asthma or nasal polyposis with sound immunity but predominantly Th2 response (i.e. strong antibody response), and smokers with COPD often have recurrent maxillary sinusitis that is or appears to be purulent.
  • Patients with asthma or nasal polyposis have chronic mucosal oedema complicating ultrasound diagnosis of maxillary sinusitis; in suspected immunodeficiency, diagnosis by puncture and aspiration should be preferred.
  • In maxillary sinus puncture, bacterial culture of the washings often remains negative even in cases appearing purulent. However, in patients with nasal polyposis Staphylococcus aureus is often found by aspiration.
  • In the most severe form of nasal polyposis, the patient also has asthma and aspirin intolerance (aspirin-exacerbated respiratory disease, AERD). If the patient has severe symptoms, the possibility of and need for aspirin desensitization therapy should be assessed by an allergy unit.
  • Even if the disease appears to be purulent, recurrent maxillary sinusitis diagnosed based on the clinical picture alone is usually due to chronic allergic rhinitis (and conjunctivitis and throat pain) predisposing the patient particularly to maxillary sinus symptoms due to viral infection. Nasal steroids and irrigation performed by the patient (neti pot or nasal syringe) should be offered for treatment.
  • Unrepaired structural obstruction of the maxillary sinuses predisposes the patient to purulent inflammations. The need for surgery should be assessed by an otologist.
  • COPD, asthma and atopy as such are associated with a 2 to 3 times higher risk of pneumococcal pneumonia, in particular. In addition, they predispose the patient to recurrent, partly viral inflammatory symptoms in the maxillary sinuses and bronchi, for which periodic or increased doses of asthma medication and nasal steroids may be useful.
  • In patients with asthma or atopy, the total serum IgE levels are usually increased, and these patients may have IgE class antibodies to allergens.
    • In more severe hypogammaglobulinaemias, about 75% of patients have no measurable IgE concentrations (serum IgE < 2), and only about 5% of patients with CVI produce IgE antibodies against allergens.

Replacement therapy of antibody deficiency

• If clinically significant antibody deficiency is diagnosed, permanent immunoglobulin (IgG) replacement therapy is necessary. Replacement therapy is administered either intravenously at a hospital or subcutaneously at home (usually 0.4-0.8 g/kg/month).
• It is particularly important to treat severe antibody deficiency such as
  • CVIs, other rare genetic hypogammaglobulinaemias
  • agammaglobulinaemias.
• IgG replacement is effective and cost-effective.
  • Treatment has increased patients' life expectancy by decades.
  • Bronchiectasis, sepsis and pneumonias can be prevented by early initiation of IgG replacement therapy.
• IgG replacement and reimbursability of the treatment are assessed in a specialist outpatient clinic at a central or university hospital.
  • Treatment is planned based on symptoms, findings, associated diseases and target organ damage.
• Some antibody deficiencies that are less severe than CVIs are assessed in a specialist clinic and treated by IgG replacement:
  • IgG deficiency ("potential CVI"): reduced antibody response to unconjugated pneumococcal vaccine (Pneumovax^® ), clinical picture resembling CVI ("IgG hypogammaglobulinaemia")
  • "Specific antibody deficiency" (SAD): Normal IgG concentration, reduced antibody response to unconjugated pneumococcal vaccine (Pneumovax^® ), significant susceptibility to infections
  • Normative scoring systems for such milder antibody deficiencies have been described but not formally tested.
• Adult patients with antibody deficiency should be monitored and receive special treatment in a unit specializing in infectious diseases.

Other treatment of patients with antibody deficiency

• Experience shows that outpatients with, for example, respiratory tract infections benefit from courses of antimicrobial treatment that are started early and continued for longer than normal (e.g. 1.3 × the normal duration).
• In patients with antibody deficiency who are on replacement therapy, diagnosis of infections is based on direct detection (culture, staining, nucleic acid tests) and imaging.
  • Serological tests are of no use, as they only show antibodies that have been given.
  • Autoantibody tests may be useful.
  • As > 90% of patients with antibody deficiency do not form allergen-specific IgE antibodies after eruption of the disease, allergy tests (RAST, skin prick tests) are not diagnostic.
• Physical exercise and therapeutic drainage of the lungs are useful in preventing pneumonia in patients with bronchiectasis.
• Supportive psychiatric care may be useful to help patients adapt to severe chronic disease.

Other primary immune deficiencies in adults

• In addition to antibody deficiencies, other rare forms of primary immune deficiency may occur in adults. Diagnosis and monitoring of such deficiencies is concentrated in immune deficiency units at university hospitals.
• The clinical pictures and the patients' infections resemble those seen in, for instance, patients with haematological disease, organ transplant recipients and/or patients with HIV.
• If a justified suspicion of such a clinical picture arises in a basically healthy, HIV-negative adult, an immune deficiency unit at a university hospital should be consulted.

Secondary susceptibility to infections