Chapter 6 Respiratory infections and immune insufficiency
OVERVIEW
Respiratory infections are caused by pathogenic invasion and colonisation.1 Upper respiratory tract infections (URTI) involve the nose, sinuses, pharynx or larynx, while lower respiratory tract infections (LRTI) involve the lungs and bronchi, and include pneumonia, lung abscess, acute bronchitis and bronchiectasis.
The term coryza, (the common cold) encompasses for a number of viral URTIs with heterogeneous presentation.1 They may in turn lead to secondary LRTI, or predispose to bacterial URTI. The common cold is most frequently experienced with nasal congestion and drainage, sneezing, sore or scratchy throat, cough and general malaise.1,2 Influenza is regarded as a separate disease entity, although the two often overlap.1 Manifestations of influenza commonly include fever, myalgia, fatigue, malaise, headache, pain behind the eyes, dry cough, runny nose and sore throat (see Table 6.1).3,4
Table 6.1 The symptoms of influenza and cold
| SYMPTOM | COMMON COLD | INFLUENZA |
|---|---|---|
| Onset | Gradual: 1–3 days | Sudden: within a few hours |
| Site of infection | Upper respiratory tract | Entire respiratory tract |
| Nasal congestion | Frequent | Occasionally |
| Rhinorrhea | Frequent | Occasionally |
| Sneezing | Frequent | Occasionally |
| Sore throat | Frequent | Occasionally |
| Cough | Less common | Can be quite severe |
| Chest discomfort | Mild | Pronounced |
| Fever | Rare | High |
| Myalgia | Occasional or insignificant | Severe |
| Fatigue/malaise | Mild | Long lasting |
| Headache | Rare, more mild | Prominent and severe |
| Exhaustion | Rare | Early and prominent |
Source: Adapted from Meissner 20053 and Roxas & Jurenka 20075
Respiratory tract infections (RTIs) are among the most commonly experienced illnesses, and place large economic costs on the community in terms of absences from work and school, and also in visits to medical professionals.1,2 While most are self-limiting and resolve within time, they can be quite serious. Influenza kills approximately 36,000 in the United States of America every year,3 with higher mortality rates in the elderly, who have weaker immune systems.6 Many more Americans (exceeding 200,000) experience complications that require hospital admission.3
URTIs are more commonly experienced in the cooler months of the year, and in the rainy periods of tropical areas.1 Children contract a greater number of infections throughout the year than adults, possible due to their close socialisation in day care and at school.3,7
Transmission occurs by one of three main methods:1–37
Most acute respiratory illnesses are viral in origin.8 There are several viruses which cause the common cold, with rhinoviruses (HRV) playing a prominent aetiological role.1,2,9 In autumn, the peak time for colds, the HRV accounts for up to 80% of URTIs.10 Other predominant viral agents include respiratory syncytial virus (RSV), influenza virus (INF) and parainfluenza viruses (PIV).1,3,8
Genetics play a large role in immune function, and innate resistance to infection is principally inherited rather than acquired.11 The set of host genes controlling this is termed the ‘resistome’, and this varies from person to person.11 Defective genes in the resistome present most strikingly in congenital immunodeficiency syndromes, but variance in the genetic set may also lead to variability in the individual capacity of resistance to infections.12,13
Epidemiological data and the evidence from viral-challenge studies suggest that psychological stress is a risk factor for the development of URTI.14
Diet also has a key role in immune capacity. Malnourished children in developing countries, particularly those with vitamin A deficiency, are at far higher risk of contracting respiratory infection and also experience more severe morbidity.15 Many nutrients play a role in responding to microbial and viral challenge, and deficiencies in zinc, vitamin A, C, B6, iron, copper, selenium, protein intake and omega 3 fatty acids have all been shown to negatively affect immune capacity.6,16–21
Environmental chemicals are known to be immunotoxic and children exposed to these chemicals at an early age (pre- and postnatally) experience higher rates of respiratory infection than comparative populations with low levels of exposure.15,22
An inverse relationship has been demonstrated between the level of physical activity and the number of URTIs experienced by adult males.23 However, while moderate exercise enhances immune function and lowers the risk of URTI, intensive exertion actually produces a temporary suppressive effect on both the adaptive and the innate systems.24
Traditional knowledge links the development of URTI with a drop in body temperature due to cold exposure. This connection was examined in healthy subjects, who each received a 20-minute foot chill at 10°C. Approximately 29% of those receiving a foot chill were diagnosed with a cold 4 days after the chill experience, compared to 9% of control subjects (a significant difference).25 In another study, a clear connection was demonstrated between the incidence of URTI and LRTI and decreases in average ambient temperature.26
PATHOPHYSIOLOGY
The pathogenesis of URTI differs depending on the organism, but generally involves interaction between viral replication and the host immune inflammatory response.1 Viral infection stimulates a local inflammatory response, which causes the classic symptoms of the common cold—rhinorrhea and nasal obstruction.1,9 Sneezing and excess mucus production are precipitated by increased cholinergic stimulation in the area.1 Inflammatory mediators interleukin (IL) 6 and IL-8 appear to be particularly involved, with some studies correlating their concentration in nasal secretions directly with the severity of cold symptoms.27,28
Contrastingly, influenza viruses inhabit and replicate in the epithelium of the tracheobronchial area.4 Here they generate a similar inflammatory response, but also cause overt epithelial toxicity, which contributes to the severity of symptoms.4,9
CONVENTIONAL TREATMENT
As the common cold is caused by a multitude of different virus types with varying pathogenic mechanisms, a universal medical treatment remains elusive. Until more effective antiviral treatments are available, the treatment of choice for URTIs remains rest, increased fluids and symptomatic relief (usually with over-the-counter medications).29
Nasal congestion and rhinorrhea are the two most vexing symptoms of URTI, and are often addressed with intranasal or oral decongestants (see Table 6.2).30 Sneezing and rhinorrhoea may be treated with first-generation (but not second-generation) antihistamines though these drugs have no role in shortening the duration of the virus.30,31 Non-steroidal anti-inflammatory drugs are effective at reducing soreness of the throat, cough and systemic effects of URTI such as fever and malaise.32 Cough medications, both antitussives and mucolytic agents, are also frequently used, although their efficacy seems variable and limited.33
Table 6.2 Conventional symptomatic treatment of URTI
| URTI SYMPTOM | TREATMENT GOAL | PHARMACOLOGICAL TREATMENT |
|---|---|---|
| Nasal congestion | Reduce inflammation and size of nasal turbinates | Decongestants |
| Rhinorrhoea | Reduce seromucous gland secretion | |
| Reduce goblet cell exocytosis | Antihistamines (?) | |
| Sneezing | Suppress the sneeze reflex | Antihistamine (1st generation) |
| Sore throat | Reduce pain sensation and diminish pain-invoking cytokines | |
| Cough | Suppress cough reflex | Opiates (antitussive) |
| Reduce cytokines (prostaglandins)? | NSAIDs | |
| Malaise, fatigue and other systemic symptoms | Reduce responsible mediators | NSAIDs |
Source: Adapted from Gwaltney 200232
Antibiotic use is contentious in the treatment of URTI. The general consensus is that there is no benefit in treating the common cold with antibiotics.34 Most studies show no difference in symptom improvement between those treated with antibiotics immediately and those with delayed prescriptions.35 However, in patients who are more predisposed to complications, such as those with underlying lung disease, evidence does exist to support the use of these drugs in the treatment of URTIs.34,36
At present, specific antiviral treatments for respiratory viruses are commercially available only for influenza viruses.37 Because of the leading role of rhinoviruses in the common cold, effective antivirals against these viruses could be expected to have the greatest effect in the treatment of this disease. Although these agents exist, they are still in the developmental stages, and often are not as clinically efficacious as in vitro studies would suggest; they must be taken early and frequently in order to have an effect, and it is often too late by the time a patient presents to their general practitioner.2
KEY TREATMENT PROTOCOLS
From a clinical perspective, it is important to address the acute presentation first. Amelioration of symptoms, limitation of causative pathogens, and strengthening immune defences and clearance will address the patient’s immediate concerns and help them to feel better. Once this is resolved, the practitioner should endeavour to restore the health and wellbeing of the patient, and address causes of immune insufficiency that may predispose to future infections.
Addressing the symptoms
While it is important to take a holistic view of the disease process and underlying causes, symptomatic treatment of URTI is also essential (see Table 6.3). Clearing the infection and ameliorating the symptoms can be accomplished concurrently. Overall, many symptoms are the result of an inflammatory response, and thus reducing this will address the symptom cluster as a whole.
Quercetin demonstrates a potent ability to inhibit inflammatory cytokine and chemokine production in acute and chronic inflammation, including the cytokines IL-6 and IL-8, which are both implicated in the aetiology of cold symptoms.38,39 Echinacea spp. may also be of use in this regard, as it is known to modulate levels of these two cytokines.40 (See ‘Immune modulation—humoral and cellular immune system’ below.)
For the protocols for addressing symptoms such as phlegm, cough and nasal congestion, please refer to Chapter 8 on congestive respiratory illness.
Fever management
Overview
Fever is a state of elevated core temperature, which is part of the defensive response to the invasion of live or inanimate matter recognised as pathogenic or alien.46 This response is a complex physiological reaction involving a cytokine-mediated rise in core temperature, generation of acute phase reactants, and activation of numerous physiological, endocrinological, and immunological systems (see Figure 6.1).46
Figure 6.1 Hypothetical model for the febrile response. IL indicates interleukin; TNF, tumour necrosis factor; IFN, interferon; and PGE2, prostaglandin E2.46
Accompanying the development in antipyretic therapies such as external cooling and specific pharmacological antipyretic agents has come a change in medical philosophy: from fever as a beneficial host defence mechanism to fever as a symptom indicating the need for aggressive therapy.47
Treating fever presentation with antipyretic medication is commonly considered by the medical community to do no harm, nor to slow the resolution of common viral and bacterial infections.48 However, other data suggest a beneficial effect from fever and, correspondingly, adverse effects from antipyretics on infection outcomes. A positive correlation was found between maximum temperature on the day of bacteraemia and survival in a retrospective analysis of 218 patients with bacteraemia.49 In an examination of factors influencing the prognosis of spontaneous bacterial peritonitis, a positive correlation was identified between a temperature greater than 38°C and likelihood of survival.50 Paracetamol may potentially prolong chicken pox, as treated subjects experience a longer time to total crusting of lesions than placebo-treated controls,51 possibly allowing for a longer period of viral spread. Adults infected with rhinovirus exhibit more nasal viral shedding when they receive aspirin than when administered placebo.52 A trend towards longer duration of rhinoviral shedding was found in association with antipyretic therapy, showing that the use of aspirin or paracetamol is associated with suppression of the serum neutralising antibody response, and increased nasal signs and symptoms.53
An open, randomised, prospective clinical trial compared an aggressive fever treatment strategy (650 mg paracetamol every 6 hours for fever > 38.5°C and cooling blanket added if > 39.5°C) with a permissive strategy (treatment reserved for fever > 40°C only) in stable but critically ill patients. The aggressive treatment group had a higher number of infections compared with the permissive treatment group and a slightly higher rate of antibiotic use. No significant difference in the length of ICU stay was observed. However, the study was ceased prematurely due to safety concerns, after interim analysis revealed an excess mortality rate of 16% (seven of 44) in the aggressive group compared with 3% (one of 38) in the permissive group.47
Naturopathic management of fever
This has led some researchers to suggest that fever suppression may be potentially harmful, and that treating moderate fever with antipyretic or direct cooling therapies may be counterproductive.54 Key pyrogenic cytokines have also demonstrated immune-potentiating capabilities that may in theory enhance resistance to infection, lending credence to the idea of fever as beneficial.55
However, the potentially life-threatening nature of fever also needs to be emphasised and respected. Full use should be made of current medical understanding and diagnostic techniques to ensure the fever is not related to a serious condition. Close monitoring of the fever should also be employed, to ensure it stays within an acceptable range (up to 38.9oC),55 although this can vary in significance depending on whether the fever is deemed to be continuing to rise (the patient feels chilled, indicating they have not reached the new temperature set point) or has reached a peak and has started to fall (the patient feels hot).55
According to traditional herbal principles, first line treatments for fever have a ‘normalising’ effect, being regarded as mildly heating diaphoretics. Herbal examples of these include Achillea millefolium, Verbena officinalis, Hyssopus officinalis, Tilia europaea, Sambucus nigra, Eupatorium perfoliatum, Thymus vulgaris, Nepeta cataria, Tanacetum vulgare, Melissa officinalis, Oxalis acetosella and Polygonum bistorta.41,43
It is possible that a fever may require enhancement if it is considered that it is not adequately materialising, and sufficient effort has also been made to ensure there is no underlying pathology or life-threatening infection.41,43 Here moderately warming/circulation-stimulating remedies such as Cinnamomum zeylanicum, Allium sativum and Elettaria cardamomum can be used readily. Stronger heating remedies like Capsicum spp., Zingiber officinale and Armoracia rusticana require additional care as they can prove more stimulating to the fever process.41
Just as there may be reason to enhance a fever, it is possible that it may need to be controlled. In this instance cooling bitters are recommended, for example Taraxacum officinale, Cinnamomum cassia, Gentiana lutea and Andrographis paniculata.41,43
One trial found that zinc supplementation resolved fever 3.1 times more rapidly in 2- to 24-month-old boys.56 It is suggested that this nutrient is most beneficial in treating fever when the patient has sub-optimum zinc serum levels (see Table 6.6 for a review of the evidence).
Table 6.6 Review of the major evidence
Address pathogens
For a discussion of the role of antimicrobials, antivirals and antifungal agents in respiratory illness, refer to Chapter 8 on congestive respiratory illness.
Immune modulation—humoral and cellular immune system
Any factor which depletes immune function may predispose a person to develop a RTI, and those who suffer immune insufficiency, such as the elderly, those with co-existent disease, and the immunocompromised are particularly at risk of recurrent or severe infection.57
The causes of lowered innate and adaptive immune resistance are multiple and dynamic in interaction, and immune resistance varies throughout life58 (see ‘Immunity’). The innate homeostasis of individual immune response is influenced by genes, stress, diet, environmental influences, age and prior infection or inflammatory events.58
Adequate host defence mechanisms play a role in the symptom severity and clinical outcome of URTIs. While both specific and humoral immunity are important in host response to rhinoviral infection, it seems that the innate response is dominant early after infection, and modulates the symptomatic presentation.9 This is also the division that is responsible for immunosurveillance of pathogens, and for preventing initial entry.59 Thus, it is important to strengthen this general defence mechanism.
Antigen-specific humoral and cellular immune responses to URTI are elicited, but are generally not detectable until after symptoms have abated.9 Thus, enhancement of these systems is more relevant with regard to prevention of re-infection.
Vitamin C has been shown to reduce the incidence and improve the outcome of a number of infections, including RTI.19 A Cochrane review suggests that vitamin C supplementation is consistently associated with a modest reduction in the duration and severity of colds.60 The results were most positive in those trials using high doses of 8000 mg daily or more. This intervention works on a number of pathways, although not all of the mechanisms are completely understood.61,62 Vitamin C is known to be a regulator of redox and metabolic checkpoints that organise the activation and continued survival of immune cells.19 Ingestion of buffered vitamin C has been shown to significantly enhance both natural killer cells’ numbers and activity,63 and may also enhance T- and B-cell function, suggesting benefits for adaptive immunity and prophylaxis.63
Vitamin C may also ameliorate symptoms via its influences on cytokine production, as it inhibits the expression of IL-6 in particular.64 Other studies show effects on phagocyte function, production of interferon and gene expression of monocyte adhesion molecules, thereby enhancing immune function.16,61,65
Nitric oxide (NO) production by epithelial cells has shown a clear role in the body’s antiviral responses9 and reduces epithelial cell release of cytokines and chemokines induced by viral infections.66 Vitamin C has demonstrated the ability in cell lines to increase NO production, and thus may aid in viral clearance and symptom reduction via this mechanism.67
Arginine, the physiological precursor for NO, may also be a novel supplement consideration in this area.68
One of the most widely used immune modulating nutrients is zinc. Low levels of this mineral affect almost all aspects of innate and adaptive immunity. It is crucial for the development and function of natural killer cells, phagocytes, macrophages and neutrophils and lack predisposes a person to lymphocytopenia, reduced type 1 T helper (Th1) cells, and decreased thymic function.16,69–71 Prolonged states of deficiency effectively ‘reprogram’ the immune system, by increasing glucocorticoid secretion, which accelerates pre-T-cell and pre-B-cell apoptosis.72 Zinc is also essential for cytokine production and secretion.16,69–71
Several studies have demonstrated that zinc administration (up to 30 mg) is effective to ameliorate symptoms, shorten duration and decrease incidence of respiratory infections.19,73 In children, preventative zinc supplementation (at varying doses) may decrease episodes of RTI by approximately 15%, increasing to 25% in a zinc-deficient population.74,75 The most bioavailable forms of zinc supplementation appear to be glycinates, gluconates and zinc-enriched yeast.76–78
Reviews conclude that the effectiveness of zinc lozenges remains to be established. About half of studies seem to indicate beneficial effects, but a number of these fail to meet rigorous design criteria.79–81 Zinc nasal gel, however, has shown efficacy in reducing the duration of cold symptoms.82
Quercetin may be a useful additional supplement in acute respiratory illness. It seems to exert antiviral effects via Th1:Th2 modulation, encouraging the production of Th1-derived cytokine INF-γ, which eliminates or blocks viral replication in infected cells.83 Studies suggest that doses of up to 1000 mg/day may protect athletes from URTI in the period of immune depletion following heavy exertion.84,85 The mechanism seems to be directly antiviral, rather than correction of immune dysregulation.59 There is some evidence that quercetin supplementation may decrease expression of IL-886—possibly reducing nasal inflammation in the common cold. In influenza, it may protect the lung from the damaging free radicals generated in the disease process.87
Low levels of vitamin A cause a wide range of immunological defects, and may predispose a person to develop respiratory (and other) infections.16,88 Theoretically, vitamin A should be of benefit in LRTI due to its ability to up-regulate Th1 and down-regulate Th2-mediated immune responses.89 The nutrient also enhances innate defences by supporting healthy mucosal barriers and the function of macrophages, neutrophils and natural killer cells.90 However, although a Cochrane review in 2008 found that supplementation of this nutrient could prevent LRTI in retinol-deficient children or those with a poor nutritional status, evidence did not that it could beneficially affect other LRTI symptoms.89 One factor which may be responsible for this puzzling result is that many of these studies were mega-dose studies, and vitamin A supplementation seems more efficacious when administered via frequent low-dosing.89,90
The immunological activity of different herbal medicines is being increasingly documented, with labels such as ‘immuno-stimulant’ and ‘immune-enhancer’ being ascribed to herbs such as Echinacea spp.91 While ‘stimulation’ of certain immunological systems does occur, the term ‘immuno-modulation’ is perhaps more apt, as the modulation of the immune system by phytoconstituents is more complex than a purely ‘stimulating’ effect. Various plant constituents modulate the humoral and/or the cellular components of the immune system.92 While up-regulating the humoral immune system (increasing macrophage activity and phagocytosis) is often beneficial in cases of pathogenic challenge or in a deficient immune system, the workings of the cellular immune system are more complex. Some studies show that herbal medicines may ‘up’ or ‘down’ regulate varying aspects of the cellular immune system, and in isolation some constituents may modulate cytokines that individually are anti-inflammatory and/or inflammatory.∗
Herbal medicines modulate a unique combination of immune pathways, with different medicinal plants often used for similar therapeutic outcomes (e.g. acute infection). They express varying biological activities to achieve this effect. Herbal medicines may enhance the activity of immune components that are beneficial in fighting pathogens via increased humoral activity; natural killer cell, leukocyte, selective cytokine and immunoglobulin production; modulation of Th1 and Th2 cells; and/or down-regulation of NF-κB and TNF-α91 (see Table 6.4).
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