Fungal infections of the lungs



Overview

Lung diseases caused by direct invasion of fungi are characterized by respiratory symptoms such as cough, sputum, hemoptysis, fever, etc., while a few may be asymptomatic, depending on the type of disease, different treatment measures are taken, and most of them are based on antifungal medication. The prognosis varies greatly, and is related to the type of fungus, the immune status of the body, and other factors.

Definition

Pulmonary fungal infection refers to the invasion and parasitization of bronchial tubes and lungs by fungi, which directly causes or allergy leads to lung and bronchial tube damage, necrosis, etc. [1].

Broadly speaking, fungal infection of the lungs is a state of infection, more descriptive of a state of coexistence between pathogenic bacteria and the body, and is not a real disease, which has been gradually used less and less, and replaced by the concept of “pulmonary fungal disease”.

The concept of “pulmonary mycosis” emphasizes more on the pathological changes and pathophysiological process of fungi causing lung tissue damage, organ dysfunction and inflammatory reaction.

However, since there are some patients with microbiologic evidence that do not meet the diagnostic criteria for the disease [2-3], both possibilities will be described in this article to differentiate them from pulmonary mycoses.

Most fungi do not cause human-to-human transmission, and a few (e.g., Histoplasma, Penicillium marneffei, etc.) are somewhat infectious but clinically rare.

Classification

There are many ways to classify fungal diseases, such as according to the route of infection, fungal pathogenicity, morbidity, etc. In addition, it can also be classified according to the fungal species and the degree of impairment of the human immune function, etc. [3-5].

Classification according to the route of infection

Exogenous pulmonary fungal infection

Lung fungal infections are caused when fungi present outside the body are inhaled into the lungs.

Secondary pulmonary fungal infections

This refers to opportunistic infections caused by parasitic fungi after the body’s immunity has declined, or infections caused by fungal infections in other parts of the body that spread to the lungs via the lymphatic or bloodstream.

Classification according to the pathogenicity of the fungus

Lung infections caused by pathogenic fungi

Also known as true pathogenic fungi, infectious fungi, mainly Histoplasma capsulatum, Coccidioides immitis, Paracoccidioides immitis, Dermatophytes, and Sporothrix.

Lung infections caused by conditionally pathogenic fungi

Also known as opportunistic fungi, such as Candida spp, Aspergillus spp, Cryptococcus spp, Trichoderma and Penicillium spp, Pneumocystis spp, etc.

Classified according to onset

Non-invasive pulmonary fungal infections

Includes cryptogenic pulmonary fungal infections or allergic lesions caused by long-term parasitization of fungi.

Invasive pulmonary fungal infections

Damage caused by direct invasion of fungi into the trachea, bronchus and/or lung tissue.

Pathogenesis

Pulmonary fungal infections account for the first place among deep fungal infections (about 60%) and 10% to 15% of nosocomial acquired pneumonia [1]. The incidence of fungal infections of the lungs is increasing year by year due to various reasons such as aging population, organ transplantation, and the use of ultra-broad-spectrum antibiotics [4].

The vast majority of the pathogens of pulmonary fungal infections in China are conditionally pathogenic fungi [5], with Candida and Aspergillus being the most common, followed by Cryptococcus neoformans; the main true pathogenic fungi are Histoplasma capsulatum and Coccidioides immitis [6-8].

Etiology

Pathogenesis

Pulmonary fungal infections are caused by infection of the lungs by a variety of fungi (commonly, e.g., Pseudomonas, Aspergillus, Cryptococcus, and Sporothrix), and the mechanisms of pathogenic and conditionally pathogenic fungi are not entirely consistent [6-8].

Pathogenic fungi are mostly fungi attached to the surface of soil, environment, bird droppings attachment, food, etc., which multiply and produce spores, and enter the lungs through respiratory inhalation, etc., or fungi infected in other parts of the body, which flow through the lungs with the blood or lymphatic circulation.

Pathogenic fungi mainly cause exogenous infections and may invade immunocompetent individuals, often with a geographic distribution.

Conditional pathogenic fungal infections are mostly endogenous infections, mainly caused by fungi colonized in the body, closely related to the lowering of body resistance and dysfunction of bacterial flora, often occurring in patients with long-term application of broad-spectrum antibiotics, hormones, immunosuppressive drugs, tumor chemotherapy drugs and after radiotherapy.

High risk factors

Lung fungal infections are related to the immunosuppressive state of the body.

Patients without immunosuppressed state

Patient Factors

Age ≥ 65 years.

Presence of fungal colonization, especially multisite colonization.

Immunocompromised state (e.g., malnutrition, diabetes mellitus, renal insufficiency).

Treatment-related factors

Various invasive operations in the recent past.

Prolonged use of 3 or more antimicrobial drugs.

Prolonged immunosuppressive therapy.

Continuous glucocorticoid therapy for more than 3 weeks.

Patients with immunosuppressed status

Patients with hematologic malignancies, HIV infection, bone marrow transplantation or hematopoietic stem cell transplantation.

High-risk solid organ transplant recipients, patients with secondary bacterial infection after transplantation, patients requiring dialysis after transplantation.

Other patients who have had a fungal infection in the same ward within 2 months.

Pathogenesis

The pathogenesis of fungal infections of the lungs is not well understood. It is currently believed that its pathogenesis is related to host factors, pathogen factors and other factors.

Host factors

At the initial stage of fungal colonization in the lungs, the host defense system is normal and can phagocytose and kill the fungus. When the body’s immune defense function declines or is lost, the fungus cannot be removed in time and the disease is caused.

Pathogen factors

After the fungus colonizes the lungs, it produces virulence factors that inhibit the body’s immune defense function and weaken cellular immunity, thus leading to fungal infection in the lungs.

Symptoms

Clinical manifestations of pulmonary fungal infections vary widely, with fever and respiratory symptoms (e.g., cough, sputum, hemoptysis, etc.) being the most common, while insidious infections may be asymptomatic. Symptoms associated with pulmonary fungal disease can be found in the term pulmonary fungal disease.

Main symptoms

Symptoms of respiratory infection are most often manifested.

Fever

Fever is often preceded by chills and chills; it may be high, usually with an axillary temperature of 38°C or more, and is ineffective with aggressive anti-bacterial therapy.

A small number of weaker people with fever is not obvious, or even no fever.

Cough and sputum

Cough may be paroxysmal or persistent, and in severe cases, the cough is severe and persistent, which may affect sleep.

The sputum is often thick, jelly-like, and can be pulled into threads.

Shortness of breath

This is characterized by increased respiratory rate and labored breathing.

In severe cases, there are symptoms of hypoxia such as dyspnea and cyanosis.

Chest pain

It can be caused by severe cough or combined with pleurisy, mostly related to respiratory movement, and chest pain is obvious when taking deep breaths.

Complications

Diffuse pulmonary fibrosis

Prolonged fungal infection in the lungs may lead to pulmonary fibrosis, even diffuse pulmonary fibrosis.

Patients may experience symptoms such as chest tightness, dyspnea, and in severe cases, respiratory failure.

Lung abscess, pyothorax

Can be caused by localized inflammation in the lungs that irritates the pleura and causes exudation, leading to pleural effusion.

It can also be seen in severe infections when fungus enters the pleural cavity to produce purulent exudate, commonly known as pyothorax, with symptoms such as high fever, dyspnea, and mucopurulent sputum, and in severe cases, thoracentesis is required to drain the chest.

Pulmonary embolism

It is common in angiophilic Trichoderma infections, which can easily invade blood vessels and cause local embolism of pulmonary blood vessels. Symptoms include hemoptysis, chest pain and dyspnea.

Fungal infections in other parts of the body

Fungus can cause fungal infections in other parts of the body such as central nervous system, cardiovascular system and digestive system through lymphatic reflux and bloodstream dissemination.

Corresponding symptoms of other parts of the body may appear, such as dizziness, headache, convulsions, and impaired consciousness after infection of the central nervous system; palpitations, chest tightness, and shortness of breath after infection of the cardiovascular system; abdominal pain and diarrhea after infection of the digestive system, etc. The patient may suffer from respiratory failure, circulatory failure, and diarrhea.

Patients may suffer life-threatening complications such as respiratory failure, circulatory failure, heart failure, pericardial tamponade, gastrointestinal perforation and so on.

Consultation

Department of Medicine

Respiratory Medicine

When coughing, sputum, chest pain, etc. occur, it is recommended to consult a respiratory physician promptly.

Emergency Department

In case of hemoptysis, dyspnea, unconsciousness, high fever, etc., it is recommended to go to the Emergency Department immediately.

Preparation

Preparation for medical treatment: registration, preparation of documents, common problems.

Tips for seeking medical treatment

Chest X-ray or chest CT is often needed. It is recommended to wear loose clothing and inform the doctor if you are pregnant or planning to become pregnant.

If you have fever, it is recommended that you keep a record of the temperature change and try not to use fever-reducing medication on your own, so as not to affect the judgment of your condition.

Preparation Checklist for Doctor’s Visit

Symptom checklist

Especially need to pay attention to the time of symptom onset, special performance, etc.

Is there fever? What is the highest temperature?

Is there a cough? What kind of cough? How long has the cough lasted?

Is there phlegm? What color is the phlegm?

Is there chest pain? What makes it worse or relieves it?

How long have these symptoms been present?

List of medical history

Is there diabetes, malnutrition, chronic lung disease, etc.?

Is there a history of fungal infections elsewhere in the body?

Any long-term use of antibiotics, glucocorticoids, immunosuppressants, etc.?

Has there been radiotherapy treatment?

Is there any history of surgery or trauma?

Checklist

Test results in the past six months, which can be brought to the doctor’s office

Laboratory tests: blood test, calcitoninogen, serum 1,3-β-D-glucan test (G test), serum galactomannan test (GM test), etc.

Imaging tests: chest X-ray, chest CT, chest ultrasound, etc.

List of medications used

Medication used in the last 3 months, if available, bring the box or package with you to the doctor’s appointment

Glucocorticoids: e.g. methylprednisolone, prednisone, dexamethasone, etc.

Immunosuppressants: e.g. cyclophosphamide, cyclosporine, monoclonal or polyclonal antibodies, etc.

Chemotherapy drugs: e.g. carboplatin, cisplatin, etc.

Diagnosis

The diagnosis of fungal infection in the lungs first requires a clinical diagnosis of lung infection based on a comprehensive analysis of relevant information such as history, symptoms, signs, laboratory and imaging examinations, and further pathogenetic examination and even lung tissue biopsy to confirm the diagnosis [6-8].

Diagnosis is based on

Medical history

The following medical history may provide important clues and diagnostic basis.

Long-term use of hormonal and immunosuppressive drugs or suffering from immunodeficiency diseases, etc.

There are surgical procedures and mechanical ventilation.

Have a history of malignancy and radiotherapy.

Have a history of severe malnutrition or chronic lung disease.

Have a history of close contact with a confirmed or suspected fungal infection.

History of asthma or allergic diseases.

Clinical manifestations

Symptoms and signs are nonspecific and not diagnostic.

Symptoms

There are fever, cough, shortness of breath, hemoptysis and other symptoms, which may be accompanied by chest pain, loss of appetite, mental depression.

Physical signs

Observation of respiration may reveal increased respiratory rate, labored breathing, and cyanosis of the lips in severe cases.

Chest palpation may reveal increased voice tremor; if there is pleural effusion, the voice tremor is weakened.

Chest percussion may reveal turbid sounds, indicating the presence of solid lung lesions or pleural effusion.

Chest auscultation may reveal phlegm sounds and wet rales.

Laboratory Tests

Blood tests

It can understand the body’s status and is an important indicator to exclude bacterial infections.

Leukocytes, neutrophils and calcitoninogen are usually not significantly elevated in fungal infections.

Eosinophilia suggests a possible allergic state.

Calcitonin (PCT)

Calcitoninogen is generally not elevated in fungal infections.

Pathogenesis

Pathogenetics is important in the diagnosis of fungal infections [9].

Direct examination

refers to direct microscopy or fungal culture.

Direct microscopy is the most classical mycologic examination method, and the discovery of mycelium, trophozoites, and encapsulation by microscopic examination of sputum or alveolar lavage has a certain guiding significance.

Clinically commonly used is pathogen isolation and culture, which is a more reliable test for definitive diagnosis, but the culture cycle is longer, usually requiring 1 to 4 weeks. On the basis of culture, drug sensitivity test can also be carried out, which helps doctors to adjust the drug treatment program.

Indirect Tests

Two positive serum 1,3-beta-D-glucan tests (G tests) are of great diagnostic value for invasive pulmonary fungal infections other than Cryptococcus and Saprophytes.

Two positive serum galactomannan tests (GM test) are of great diagnostic value for Aspergillus infections.

A positive Cryptococcus haematobium podopolysaccharide antigen by latex agglutination is suggestive of cryptococcal infection.

Chest X-ray, Chest CT

Can provide an idea of the severity and specific lesions in the lungs and can also be used to assess recovery.

They are usually non-characteristic and may show lobar pneumonia, bronchopneumonia, nodular shadows, cavitary shadows, mass shadows, and other manifestations.

Bronchoscopy

Bronchoscopy provides a more visual and clearer picture of the trachea and bronchial tubes and the presence of lesions.

Specimens are also taken through bronchoscopy and sent for examination of related fungal infections.

Diagnostic criteria

Diagnostic criteria for specific diseases can be found in the individual terms.

As the concept of fungal disease is more commonly used nowadays, patients in whom the pathogen is found, but in whom no obvious pulmonary lesions are found, are more commonly referred to as patients with undetermined fungal disease [10].

Differential diagnosis

Bacterial pneumonia

Similarities: both can lead to symptoms such as fever, cough and sputum, and manifestations such as inflammatory exudates in the lungs are common on chest imaging.

Differences: Anti-bacterial treatment is ineffective in fungal infections of the lungs. Pathogenetic examination has important differentiation value.

Lung tumor

Similarity: Cough, sputum, fever and other symptoms.

Difference: Lung tumors often have a history of long-term smoking, chest pain, hemoptysis, enlarged peripheral lymph nodes, sputum and histopathological examination can find tumor cells, which can make a clear diagnosis.

Treatment

Aim of treatment: control and alleviate lung conditions, improve lung ventilation, eradicate fungal infection, and prevent complications.

Therapeutic principles: according to the pathogenic bacteria of the patient’s infection, choose antifungal-based comprehensive treatment, remove and drain the primary lesion as early as possible, and choose sensitive antifungal drugs for treatment [11].

Invasive pulmonary fungal infection

Antifungal infection treatment

Commonly used drugs such as posaconazole, fluconazole, itraconazole, voriconazole, etc., see the term pulmonary fungal disease.

Diagnosis-driven treatment

Antifungal therapy, also known as diagnosis-driven therapy, may be given at the discretion of the patient if any 1 of the following clinical symptoms is met, as well as any 1 of the test results, but a definitive diagnosis or clinical diagnosis has not been reached [10].

Clinical symptoms

Absence of clinical symptoms of fungal infection.

Presence of ineffective treatment with broad-spectrum antifungal medications and persistent neutrophil-deficient fever.

Examination findings

Clinical imaging signs of fungal infection in the lungs, such as the presence of Aspergillus infection-related imaging changes on chest CT.

Microbiologic hallmarks of pulmonary fungal infection, such as a positive GM/G test, positive fungal culture or microscopic examination of specimens obtained from non-sterile sites or non-sterile manipulations.

Principles of drug selection may be based on empiric therapy; drugs of choice include caspofungin, micafungin, voriconazole, itraconazole, amphotericin B and its liposomes. They should be applied at least until the temperature drops to normal, the clinical condition stabilizes, and relevant microbiological and/or imaging parameters return to normal.

The advantages of diagnosis-driven therapy are to avoid the overuse of empiric antifungal therapy based solely on fever and to ensure efficacy by initiating antifungal therapy as early as possible, based on sensitization markers associated with invasive fungal infections.

Non-invasive fungal infections

There is no standardized treatment regimen, and symptomatic treatment is the mainstay.

Lung fungal infections caused by fungal parasites, such as pulmonary histoplasmosis (HP), do not require treatment in mild cases in immunocompetent patients and may resolve spontaneously within 1 month; antifungal therapy is required in moderate or severe cases or in immunocompromised patients.

Allergic fungal infections of the lungs can be treated with glucocorticoids (e.g., dexamethasone, prednisone, etc.). Antifungal therapy plays a helpful role.

Prognosis

Cure

Most non-invasive pulmonary fungal infections can be cured; some invasive pulmonary fungal infections can lead to long-term colonization and persistent infection, making them difficult to cure.

Most cases of pulmonary histoplasmosis (HP) are self-limiting and generally have a good prognosis.

Invasive pulmonary Candida infections have a poorer prognosis with a 40% case fatality rate [5].

Invasive pulmonary Aspergillus infection, has an even worse prognosis with a case fatality rate of more than 80% [5].

Pulmonary trichinosis is aggressive and has a poor prognosis.

The prognosis of pulmonary sporotrichosis (PCP) is related to the comorbid underlying disease, with a morbidity and mortality rate ranging from 10% to 60% [5].

Pulmonary Marnefeldt-Jakob disease is prone to involve multiple organs and systems and has a poor prognosis, requiring early onset and prompt treatment.

Prognostic factors

The prognosis of different diseases is highly variable and is related to the type of fungus and the patient’s own physical condition, comorbidities, and underlying diseases, which can be found in the Pulmonary Fungal Disease entry Pulmonary Fungal Disease.

Most fungal infections of the lungs have a good prognosis when treated with prompt, aggressive, and effective medications.

Patients with serious underlying diseases such as diabetes and malignant tumors often have a poor prognosis.

Harmfulness

Most will not leave damage, the structure and function of the affected organs and tissues can be restored to normal, but a small number of them can cause necrotic lesions in lung tissue, forming cavities or fibrosis.

Daily

Daily management

Some fungal infections are contagious, patients should wear masks and try to avoid close contact with young children, the elderly, pregnant women and immunocompromised people.

Stop smoking and drinking to prevent aggravating lung damage. Alcohol may interact with medications.

Regular work and rest, avoid exertion and staying up late; balanced nutrition, sufficient water, protein and energy.

Disease monitoring

During the use of drugs, regular monitoring should be carried out, including blood routine, urine routine, liver and kidney function, electrocardiogram and so on.

Patients should be reviewed regularly, such as blood routine, liver and kidney function, chest imaging.

Pay attention to changes in the patient’s condition, and seek immediate medical follow-up if there is persistent high fever, dyspnea, cyanosis, depression, and clammy cold extremities.

Follow-up examination

About 1 week after discharge, review the blood routine, C-reactive protein, G test, GM test and other infection indexes as well as biochemical and coagulation indexes, and adjust the drug treatment program and course of treatment according to the doctor’s instructions.

Chest X-ray/CT of chest should be repeated 1 month after discharge to observe the absorption of inflammation in the lungs and its recovery.

Prevention

The relevant vaccine is still in the clinical research stage, therefore, strictly speaking, there is no targeted preventive measures. The following measures can help to reduce the possibility of lung fungal infection.

Exercise to improve the body’s immunity.

Actively treat underlying diseases.

Reasonable use of antimicrobial drugs, strict control of the dose and course of treatment.

Strictly control the dose and course of hormones.

Minimize or avoid medical factors leading to Candida infection, such as timely removal of deep vein indwelling tubes.

Immunocompromised patients should strengthen the supportive therapy.