OVERVIEW

What is pneumonia of unknown origin?

Pneumonia of unknown origin is a term introduced by the former Ministry of Health after the SARS outbreak, with the following purposes:

• Strengthen the monitoring, investigation, and outbreak response for cases of pneumonia of unknown origin;
• Timely detection of SARS and human avian influenza cases;
• Timely identification of other clustered respiratory infectious diseases primarily presenting as pneumonia.

How is pneumonia of unknown origin diagnosed?

A case can be diagnosed as pneumonia of unknown origin if it meets all four of the following criteria and cannot be clearly diagnosed as another disease:

• Fever (axillary temperature ≥ 38°C);
• Radiographic features of pneumonia (e.g., chest CT showing signs of pneumonia);
• Early-stage blood tests showing decreased or normal total white blood cell count, or reduced lymphocyte count;
• No significant improvement or worsening of the condition after 3–5 days of standard antimicrobial treatment.

What is clustered pneumonia of unknown origin?

Clustered pneumonia of unknown origin refers to two or more cases of pneumonia of unknown origin occurring within two weeks that are epidemiologically linked.

Epidemiological linkage means the patients shared living, working, or exposure environments before onset or had close contact.

Determining epidemiological linkage requires healthcare professionals to thoroughly inquire about the patients' exposure history during consultation or rely on detailed epidemiological investigations by disease control specialists.

Does pneumonia of unknown origin refer to all pneumonia cases without identified causes?

No. A pneumonia case must meet the above criteria to be diagnosed as pneumonia of unknown origin.

In clinical practice, the cause of most pneumonia cases is not (and does not need to be) identified, as empirical treatment is often sufficient for recovery.

For example, one medical study conducted intensive pathogen screening in hospitalized adult patients with community-acquired pneumonia, yet only 38%–87% of cases had a confirmed causative microorganism identified—despite specialized screening efforts.

SYMPTOMS

What are the symptoms and manifestations of pneumonia of unknown cause?

The main symptoms include cough, sputum production, fever, chills, chest pain, and difficulty breathing. For details, please refer to the disease introduction about pneumonia.

CAUSES

Is it necessary for doctors to know the cause of pneumonia when treating patients with pneumonia?

Yes, but it is sufficient to broadly infer the type of pathogen.

For doctors, identifying the pathogen of pneumonia helps in selecting appropriate medications for treatment, which is medically referred to as "empirical therapy."

If empirical therapy is effective, treatment can continue; if it is ineffective, further measures must be taken to determine the specific cause of pneumonia.

How do doctors infer the cause of pneumonia?

Generally, doctors deduce the likely cause of pneumonia based on the patient's environment. Pneumonia contracted in different environments often involves different pathogens, and the antimicrobial drugs used may vary. For this reason, doctors broadly classify pneumonia into the following categories:

• Community-acquired pneumonia (CAP): Refers to pneumonia contracted in daily living or working environments.
• Hospital-acquired pneumonia (HAP): Refers to pneumonia contracted in a hospital.
• Ventilator-associated pneumonia (VAP): Refers to pneumonia contracted while a patient is using a ventilator.

In addition to the patient's environment, their own condition can also help doctors infer the cause of pneumonia:

• Age: Children under 5 years old are more susceptible to viral pneumonia.
• Underlying diseases: For example, organ transplant patients are more prone to cytomegalovirus pneumonia.
• Lifestyle and habits: Parental smoking can increase the risk of pneumonia in children under 5.
• Vaccination status: After the introduction of pneumonia vaccines in countries like the U.S., outpatient and inpatient cases of pneumococcal pneumonia significantly declined.

When should we suspect the presence of a new pathogen?

In clinical practice, the pathogens causing about 50% of pneumonia cases remain unidentified. So when should we suspect and search for new pathogens?

Generally, if the pneumonia's transmissibility, severity, or clinical features are not particularly unusual, doctors typically do not make an effort to determine whether it is caused by a new pathogen, as doing so holds little practical significance. About 50% of pneumonia cases with unknown pathogens still improve with empirical therapy.

However, if the disease exhibits unusually high transmissibility, severity, or distinctive clinical features (e.g., Legionella infection causing hyponatremia, hematuria, or proteinuria), then the possibility of a new pathogen should be considered.

Once suspicion arises, doctors must collaborate with microbiologists, epidemiologists, and other experts to identify the pathogen as quickly as possible. This is especially critical for highly contagious pathogens.

What newly discovered pneumonia-causing pathogens have emerged in recent years?

With advances in medical technology, an increasing number of new pathogenic microorganisms have been discovered, unraveling many disease mysteries. For example:

• In 2001, human metapneumovirus was identified as a common and significant pathogen for colds, bronchitis, and pneumonia.
• In 2003, the SARS coronavirus was discovered, challenging the notion that coronaviruses were relatively low in virulence.
• In 2005, human bocavirus (HBoV) was found to be another common pathogen for colds, bronchitis, and pneumonia.
• In 2012, the Middle East Respiratory Syndrome coronavirus (MERS-CoV) was identified as the most lethal known coronavirus.
• In 2014, enterovirus D68 was recognized as one of the common pneumonia pathogens in U.S. children.
• In 2019, the novel coronavirus was discovered, leading to a global pandemic.
• …

Additionally, medical scientists have found that some viruses previously circulating among animals can also spread among humans. For example:

• In 1997, Hong Kong reported human infections with avian influenza A (H5N1), which was primarily circulating among birds. However, its transmissibility appeared limited, and it did not become a pandemic strain.
• In 2009, swine-origin influenza A (H1N1) crossed species barriers, causing a widespread human flu outbreak. It later became a common "seasonal flu" strain.
• In 2013, Huashan Hospital's infectious disease department in China identified severe pneumonia caused by human infections with avian influenza A (H7N9), previously thought to circulate only among birds. Its transmissibility was low, spreading only through close contact, hence classified as "limited" human-to-human transmission.
• Other examples include H5N6, H7N2, H7N3, H7N7, and H9N2.

Except for H1N1, which became a pandemic strain, none of the others caused widespread outbreaks in human society. It is also possible that their pathogenicity (severity and fatality rates) was relatively mild, presenting only cold-like symptoms, leading to their oversight.

DIAGNOSIS

What tests are needed for patients with pneumonia of unknown cause?

Currently, the main etiological (causal) testing methods for pneumonia include:

• Sputum culture: Obtaining sputum and culturing pathogenic microorganisms on a medium.
• Blood culture: Drawing blood and culturing pathogenic microorganisms on a medium.
• PCR: Collecting samples such as sputum or blood to perform polymerase chain reaction (PCR), identifying and confirming the nucleic acid of pathogenic microorganisms.
• Next-generation sequencing (NGS): A large-scale parallel sequencing technology that can rapidly sequence the entire genome of unknown microorganisms to determine the "identity" of the pathogen. The novel coronavirus SARS-CoV-2, which emerged in late 2019, was identified using NGS.
• Antibody testing: Collecting blood or urine to detect specific antibodies produced by the body in response to pathogenic microorganisms, thereby indirectly identifying the pathogen.

One important note: The microorganisms detected may not necessarily be the ones causing pneumonia. This is particularly important to consider when performing sputum cultures or blood antibody tests.

TREATMENT

What tasks do doctors typically need to perform after examining a patient with pneumonia of unknown cause?

There are many tasks to complete:

• Collect epidemiological history: When gathering the medical history of a pneumonia case of unknown cause, healthcare workers will pay special attention to inquiring about the patient's epidemiological history and whether there are clustered cases in their surroundings.
• Report step by step: After diagnosing pneumonia of unknown cause, healthcare workers must immediately report it to their medical institution. The institution must organize an expert panel for consultation and investigation within 12 hours. If the cause still cannot be identified, they must promptly fill out an infectious disease report card, noting "pneumonia of unknown cause," and report it to the local disease control agency.
• Refer if necessary: Primary healthcare facilities without the capacity for medical diagnosis and treatment must immediately transfer the patient to a higher-level hospital for further evaluation. The receiving hospital will then complete the infectious disease report.
• Hospitalize and isolate: Hospitals with the capability to treat such cases will admit the patient immediately upon diagnosis and implement isolation and treatment measures in accordance with standards for respiratory infectious diseases.
• Collect and send specimens: Collect samples from the patient, including nasopharyngeal swabs, lower respiratory tract specimens (e.g., tracheal secretions, tracheal aspirates), and serum samples. If the patient dies and the family consents to an autopsy (given the high risk of infectious diseases, families are encouraged to cooperate), a timely autopsy should be performed to collect tissue specimens (e.g., lung tissue, tracheal, and bronchial tissues). Collected specimens must be properly preserved for further testing.
• Register close contacts: Identify, monitor, and report close contacts of clustered pneumonia cases of unknown cause within the hospital.

DIET & LIFESTYLE

None.

PREVENTION

What protective measures should the attending doctor take when treating patients with pneumonia of unknown cause to prevent infection?

Basic personal protective measures should be taken, such as wearing work clothes, work caps, and medical protective masks.

When clusters of pneumonia cases of unknown cause are detected, immediate isolation measures for respiratory infectious diseases and corresponding hospital infection control measures should be implemented.