A 36-year-old male was admitted to a private hospital in Kathmandu with a history of fever, headache, body aches, nausea and appetite loss. Despite laboratory investigations, the cause of the fever was unidentified. He was treated with multiple broad-spectrum antibiotics and recovered uneventfully. The question remains: What was the cause of the fever? In recent years, the number of patients with undiagnosed fever cases has increased in Nepal. In 2019, fever of unknown origin (FUO) was a primary reason for hospitalisation at Sukraraj Tropical and Infectious Disease Hospital (STIDH). A fever is not an illness but rather a symptom or sign of a disease, mainly infectious. As monsoon begins, many patients with FUO are visible, highlighting how unknown infections are possibly spreading across the country without our notice.

Healthcare workers usually send blood for multiple laboratory tests to identify the microorganisms/pathogens if a person develops a fever. This practice is known as a “fever profile or panel test” among healthcare workers. However, a fever profile test includes a few test kits to identify microorganisms in a routine laboratory examination. The doctor must start treatment with multiple broad-spectrum antibiotics if the microorganism is unidentified. As a result, long-term overuse or misuse of antibiotics results in multidrug-resistant microorganisms, which delay recovery time. For instance, E. coli bacteria, a common cause of urinary tract infections, have become resistant to almost all available antibiotics in Nepal. Unfortunately, over the last two decades, I haven't seen the addition of more laboratory test kits in the routine examination to identify causative agents in febrile patients. Moreover, healthcare workers working in remote areas are compelled to diagnose diseases based on the signs/symptoms due to a lack of laboratory facilities; if the patient dies of FUO, it is declared death from a mysterious disease.

Underestimated tick bites

Instances of vector-borne fever have increased in Nepal in the past few years. During the 2019 and 2022 dengue outbreaks, hundreds of patients with unknown fever (dengue negative) were found. Mosquitoes, particularly Aedes species, are responsible for spreading the dengue virus, causing significant community outbreaks. Unfortunately, no tests are available besides dengue for other viral diseases Aedes mosquitoes can spread. Moreover, fever-causing insect/tick bites are also vastly underestimated in Nepal. Lyme disease, caused by the bacterium Borrelia burgdorferi and transmitted to humans by the bite of an infected "Ixodes" tick, was first reported in Nepal in 2017. I published a report on the issue in the journal JMM Case Report in 2018. However, unknown fever cases after tick bites are underreported in Nepal. Scrub typhus, a rickettsial disease transmitted through the bite of a chigger mite (tick), is now commonly reported in Nepal since 2015 after several children died from this bacterium. Still, the existence of other rickettsial diseases is unknown in Nepal. In 2001, Murine typhus (Rickettsia typhi) was reported in Kathmandu, highlighting the emergence of rickettsial infections. Regrettably, tests are unavailable to identify rickettsial infections—except Scrub typhus—at the moment.

Disease X

Influenza, also known as "flu", is increasingly observed in Nepal. Flu is one of the droplets/airborne viruses that cause fever. FUO cases due to droplets/airborne routes are found in high numbers. In recent weeks, around 93 percent of the patients with flu-like illness tested negative for the flu virus; this means many droplets/airborne FUO cases are emerging in Nepal. According to the World Health Organization (WHO), flu-like illness (ILI) is an acute respiratory infection with a fever over 38 degrees Celsius or 100.4 degrees Fahrenheit and an onset of cough within the last 10 days. It is worth mentioning here that the SARS-CoV-2 virus, a causative agent of COVID-19, was initially reported as a SARS-like virus (unknown fever), meaning (FUO) can potentially cause a "Disease X". As per WHO, "Disease X" refers to an unknown pathogen that can trigger a severe international epidemic or pandemic.

During the summer and monsoon, prolonged high-grade fever primarily causes hospitalisations among the people in Nepal. Water-borne infections are believed to be the leading cause behind fever outbreaks and hospitalisations. If a person develops a fever, health care workers send blood for culture or a widal test to confirm typhoid bacteria. Typhoid fever, caused by salmonella typhi and paratyphi, is usually witnessed during Nepal's summer/monsoon season. However, only a few fever cases are being confirmed as typhoid disease, indicating a large proportion of fevers of unknown origin or falling (accumulating) into the category of FUO.

Data shows that FUO is emerging and becoming a public health problem, especially as limited laboratory tests are available to identify infections in Nepal. Ultimately, using broad-spectrum antibiotics without identifying pathogens leads to drug-resistant problems and delays recovery time. FUO, as a primary reason for hospitalisation in recent years, should ignite apprehension among health officials and authorities about the future. Additionally, the authorities must invest in additional laboratory test kits (to identify more infections) and fever research to understand patterns of infectious diseases and develop strategic control plans for possible fever outbreaks of unknown origin before it is too late.