Providing basic sanitation and safe drinking water and food is the key for controlling the disease. In developed countries, enteric fever rates decreased in the past when treatment of municipal water was introduced, human feces were excluded from food production, and pasteurization of dairy products began. In addition, children and adults should be carefully educated about personal hygiene. This would include careful handwashing after defecation and sexual contact, before preparing or eating food, and especially the sanitary disposal of feces. Food handlers should be educated in personal hygiene prior to handling food or utensils and equipment. Infected individuals should be advised to avoid food preparation. Sexually active people should be educated about the risks of sexual practices that permit fecal-oral contact.

Those who travel to countries with poor sanitation should receive a live attenuated typhoid vaccine—Ty21a (Vivotif), which, in addition to the protection against typhoid fever, and may provide some protection against paratyphoid fever caused by the "S. enterica" serotypes A and B. In particular, a reanalysis of data from a trial conducted in Chile showed the Ty21a vaccine was 49% effective (95% CI: 8–73%) in preventing paratyphoid fever caused by the serotype B. Evidence from a study of international travelers in Israel also indicates the vaccine may prevent a fraction of infections by the serotype A, although no trial confirms this. This cross-protection by a typhoid vaccine is most likely due to O antigens shared between different "S. enterica" serotypes.

Exclusion from work and social activities should be considered for symptomatic, and asymptomatic, people who are food handlers, healthcare/daycare staff who are involved in patient care and/or child care, children attending unsanitary daycare centers, and older children who are unable to implement good standards of personal hygiene. The exclusion applies until two consecutive stool specimens are taken from the infected patient and are reported negative.

On infection the microorganism can be found in blood and cerebrospinal fluid (CSF) for the first 7 to 10 days (invoking serologically identifiable reactions) and then moving to the kidneys. After 7 to 10 days the microorganism can be found in fresh urine. Hence, early diagnostic efforts include testing a serum or blood sample serologically with a panel of different strains.

Kidney function tests (blood urea nitrogen and creatinine) as well as blood tests for liver functions are performed. The latter reveal a moderate elevation of transaminases. Brief elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) levels are relatively mild. These levels may be normal, even in children with jaundice.

Diagnosis of leptospirosis is confirmed with tests such as enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR). The MAT (microscopic agglutination test), a serological test, is considered the gold standard in diagnosing leptospirosis. As a large panel of different leptospira must be subcultured frequently, which is both laborious and expensive, it is underused, especially in developing countries.

Differential diagnosis list for leptospirosis is very large due to diverse symptoms. For forms with middle to high severity, the list includes dengue fever and other hemorrhagic fevers, hepatitis of various causes, viral meningitis, malaria, and typhoid fever. Light forms should be distinguished from influenza and other related viral diseases. Specific tests are a must for proper diagnosis of leptospirosis.

Under circumstances of limited access (e.g., developing countries) to specific diagnostic means, close attention must be paid to the medical history of the patient. Factors such as certain dwelling areas, seasonality, contact with stagnant contaminated water (bathing, swimming, working on flooded meadows, etc.) or rodents in the medical history support the leptospirosis hypothesis and serve as indications for specific tests (if available).

"Leptospira" can be cultured in Ellinghausen-McCullough-Johnson-Harris medium (EMJH), which is incubated at 28 to 30 °C. The median time to positivity is three weeks with a maximum of three months. This makes culture techniques useless for diagnostic purposes but is commonly used in research.

Serological testing is typically used to obtain a definitive diagnosis. Most serological tests would succeed only after a certain period of time past the symptom onset (usually a week). The differential diagnosis list includes typhus, ehrlichiosis, leptospirosis, Lyme disease and virus-caused exanthema (measles or rubella).

The diagnosis of dengue fever may be confirmed by microbiological laboratory testing. This can be done by virus isolation in cell cultures, nucleic acid detection by PCR, viral antigen detection (such as for NS1) or specific antibodies (serology). Virus isolation and nucleic acid detection are more accurate than antigen detection, but these tests are not widely available due to their greater cost. Detection of NS1 during the febrile phase of a primary infection may be greater than 90% sensitive however is only 60–80% in subsequent infections. All tests may be negative in the early stages of the disease. PCR and viral antigen detection are more accurate in the first seven days. In 2012 a PCR test was introduced that can run on equipment used to diagnose influenza; this is likely to improve access to PCR-based diagnosis.

These laboratory tests are only of diagnostic value during the acute phase of the illness with the exception of serology. Tests for dengue virus-specific antibodies, types IgG and IgM, can be useful in confirming a diagnosis in the later stages of the infection. Both IgG and IgM are produced after 5–7 days. The highest levels (titres) of IgM are detected following a primary infection, but IgM is also produced in reinfection. IgM becomes undetectable 30–90 days after a primary infection, but earlier following re-infections. IgG, by contrast, remains detectable for over 60 years and, in the absence of symptoms, is a useful indicator of past infection. After a primary infection, IgG reaches peak levels in the blood after 14–21 days. In subsequent re-infections, levels peak earlier and the titres are usually higher. Both IgG and IgM provide protective immunity to the infecting serotype of the virus. In testing for IgG and IgM antibodies there may be cross-reactivity with other flaviviruses which may result in a false positive after recent infections or vaccinations with yellow fever virus or Japanese encephalitis. The detection of IgG alone is not considered diagnostic unless blood samples are collected 14 days apart and a greater than fourfold increase in levels of specific IgG is detected. In a person with symptoms, the detection of IgM is considered diagnostic.

Diagnosis is made by any blood, bone marrow or stool cultures and with the Widal test (demonstration of antibodies against "Salmonella" antigens O-somatic and H-flagellar). In epidemics and less wealthy countries, after excluding malaria, dysentery, or pneumonia, a therapeutic trial time with chloramphenicol is generally undertaken while awaiting the results of the Widal test and cultures of the blood and stool.

The Widal test is time-consuming, and prone to significant false positive results. The test may be also falsely negative in the early course of illness. However, unlike Typhidot test Widal test quantifies the specimen with titres.

Typhidot is a medical test consisting of a dot ELISA kit that detects IgM and IgG antibodies against the outer membrane protein (OMP) of the Salmonella typhi. The typhidot test becomes positive within 2–3 days of infection and separately identifies IgM and IgG antibodies. The test is based on the presence of specific IgM and IgG antibodies to a specific 50Kd OMP antigen, which is impregnated on nitrocellulose strips. IgM shows recent infection whereas IgG signifies remote infection. The most important limitation of this test is that it is not quantitative and result is only positive or negative.

The term 'enteric fever' is a collective term that refers to severe typhoid and paratyphoid.

The World Health Organization's 2009 classification divides dengue fever into two groups: uncomplicated and severe. This replaces the 1997 WHO classification, which needed to be simplified as it had been found to be too restrictive, though the older classification is still widely used including by the World Health Organization's Regional Office for South-East Asia as of 2011. Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage while all other cases are uncomplicated. The 1997 classification divided dengue into undifferentiated fever, dengue fever, and dengue hemorrhagic fever. Dengue hemorrhagic fever was subdivided further into grades I–IV. Grade I is the presence only of easy bruising or a positive tourniquet test in someone with fever, grade II is the presence of spontaneous bleeding into the skin and elsewhere, grade III is the clinical evidence of shock, and grade IV is shock so severe that blood pressure and pulse cannot be detected. Grades III and IV are referred to as "dengue shock syndrome".

The diagnosis is made with serologic methods, either the classic Weil-Felix test

(agglutination of Proteus OX strains ), ELISA, or immunofluorescence assays in the bioptic material of the primary lesion.

Yellow fever is most frequently a clinical diagnosis, made on the basis of symptoms and the diseased person's whereabouts prior to becoming ill. Mild courses of the disease can only be confirmed virologically. Since mild courses of yellow fever can also contribute significantly to regional outbreaks, every suspected case of yellow fever (involving symptoms of fever, pain, nausea and vomiting six to 10 days after leaving the affected area) is treated seriously.

If yellow fever is suspected, the virus cannot be confirmed until six to 10 days after the illness. A direct confirmation can be obtained by reverse transcription polymerase chain reaction where the genome of the virus is amplified. Another direct approach is the isolation of the virus and its growth in cell culture using blood plasma; this can take one to four weeks.

Serologically, an enzyme linked immunosorbent assay during the acute phase of the disease using specific IgM against yellow fever or an increase in specific IgG-titer (compared to an earlier sample) can confirm yellow fever. Together with clinical symptoms, the detection of IgM or a fourfold increase in IgG-titer is considered sufficient indication for yellow fever. Since these tests can cross-react with other flaviviruses, like dengue virus, these indirect methods cannot conclusively prove yellow fever infection.

Liver biopsy can verify inflammation and necrosis of hepatocytes and detect viral antigens. Because of the bleeding tendency of yellow fever patients, a biopsy is only advisable "post mortem" to confirm the cause of death.

In a differential diagnosis, infections with yellow fever must be distinguished from other feverish illnesses like malaria. Other viral hemorrhagic fevers, such as Ebola virus, Lassa virus, Marburg virus, and Junin virus, must be excluded as cause.

Abnormal laboratory findings seen in patients with Rocky Mountain spotted fever may include a low platelet count, low blood sodium concentration, or elevated liver enzyme levels. Serology testing and skin biopsy are considered to be the best methods of diagnosis. Although immunofluorescent antibody assays are considered some of the best serology tests available, most antibodies that fight against "R. rickettsii" are undetectable on serology tests the first seven days after infection.

Differential diagnosis includes dengue, leptospirosis, and, most recently, chikungunya and Zika virus infections.

Those diagnosed with Type A of the bacterial strain rarely die from it except in rare cases of severe intestinal complications. With proper testing and diagnosis, the mortality rate falls to less than 1%. Antibiotics such as azithromycin are particularly effective in treating the bacteria.

Although commercial tests are not readily available, diagnosis can be confirmed by serology-based assays or quantitative PCR by laboratories that have developed assays to perform such identification.

The illness can be treated with tetracyclines (doxycycline is the preferred treatment), chloramphenicol, macrolides or fluoroquinolones.

A blood test is the only way to confirm a case of Ross River Fever. Several types of blood tests may be used to examine antibody levels in the blood. Tests may either look for simply elevated antibodies (which indicate some sort of infection), or specific antibodies to the virus.

Tetracycline-group antibiotics (doxycycline, tetracycline) are commonly used. Chloramphenicol is an alternative medication recommended under circumstances that render use of tetracycline derivates undesirable, such as severe liver malfunction, kidney deficiency, in children under nine years and in pregnant women. The drug is administered for seven to ten days.

The treatment for bacillary angiomatosis is erythromycin given for three to four months.

Biopsies or cultures of a person's tick wound (eschar) are used to diagnose ATBF. However, this requires special culture media and can only be done by a laboratory with biohazard protection. There are more specialized laboratory tests available that use quantitative polymerase chain reactions (qPCR), but can only be done by laboratories with special equipment. Immunofluorescence assays can also be used, but are hard to interpret because of cross-reactions with other rickettsiae bacteria.

Doxycycline has been provided once a week as a prophylaxis to minimize infections during outbreaks in endemic regions. However, there is no evidence that chemoprophylaxis is effective in containing outbreaks of leptospirosis, and use of antibiotics increases antibiotics resistance. Pre-exposure prophylaxis may be beneficial for individuals traveling to high-risk areas for a short stay.

Effective rat control and avoidance of urine contaminated water sources are essential preventive measures. Human vaccines are available only in a few countries, such as Cuba and China. Animal vaccines only cover a few strains of the bacteria. Dog vaccines are effective for at least one year.

Diagnosis of ATBF is mostly based on symptoms, as many laboratory tests are not specific for ATBF. Common laboratory test signs of ATBF are a low white blood cell count (lymphopenia) and low platelet count (thrombocytopenia), a high C-reactive protein, and mildly high liver function tests.

Diagnosis is usually based on serology (looking for an antibody response) rather than looking for the organism itself. Serology allows the detection of chronic infection by the appearance of high levels of the antibody against the virulent form of the bacterium. Molecular detection of bacterial DNA is increasingly used. Culture is technically difficult and not routinely available in most microbiology laboratories.

Q fever can cause endocarditis (infection of the heart valves) which may require transoesophageal echocardiography to diagnose. Q fever hepatitis manifests as an elevation of alanine transaminase and aspartate transaminase, but a definitive diagnosis is only possible on liver biopsy, which shows the characteristic fibrin ring granulomas.

There is no specific treatment for the disease. Pain killers and fluid replacement may be useful.

A range of laboratory investigations are performed, where possible, to diagnose the disease and assess its course and complications. The confidence of a diagnosis can be compromised by if laboratory tests are not available. One comprising factor is the number of febrile illnesses present in Africa, such as malaria or typhoid fever that could potentially exhibit similar symptoms, particularly for non-specific manifestations of Lassa fever. In cases with abdominal pain, in countries where Lassa is common, Lassa fever is often misdiagnosed as appendicitis and intussusception which delays treatment with the antiviral ribavirin. In West Africa, where Lassa is most prevalent, it is difficult for doctors to diagnose due to the absence of proper equipment to perform tests.

The FDA has yet to approve a widely validated laboratory test for Lassa, but there are tests that have been able to provide definitive proof of the presence of the LASV virus. These tests include cell cultures, PCR, ELISA antigen assays, plaque neutralization assays, and immunofluorescence essays. However, immunofluorescence essays provide less definitive proof of Lassa infection. An ELISA test for antigen and IgM antibodies give 88% sensitivity and 90% specificity for the presence of the infection. Other laboratory findings in Lassa fever include lymphopenia (low white blood cell count), thrombocytopenia (low platelets), and elevated aspartate aminotransferase levels in the blood. Lassa fever virus can also be found in cerebrospinal fluid.

The diagnosis of relapsing fever can be made on blood smear as evidenced by the presence of spirochetes. Other spirochete illnesses (Lyme disease, syphilis, leptospirosis) do not show spirochetes on blood smear. Although considered the gold standard, this method lacks sensitivity and has been replaced by PCR in many settings.

This condition is diagnosed by detecting the bacteria in skin, blood, joint fluid, or lymph nodes. Blood antibody tests may also be used. To get a proper diagnosis for rat-bite fever, different tests are run depending on the symptoms being experienced.

To diagnosis streptobacillary rat-bite fever, blood or joint fluid is extracted and the organisms living in it are cultured. Diagnosis for spirillary rat bite fever is by direct visualization or culture of spirilla from blood smears or tissue from lesions or lymph nodes. Treatment with antibiotics is the same for both types of infection. The condition responds to penicillin, and where allergies to it occur, erythromycin or tetracyclines are used.

Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and had been reported to last for at least 10 years. WHO now states that a single dose of vaccination is sufficient to confer lifelong immunity against yellow fever disease." The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler. The World Health Organization (WHO) recommends routine vaccinations for people living in affected areas between the 9th and 12th month after birth.

Up to one in four people experience fever, aches, and local soreness and redness at the site of injection. In rare cases (less than one in 200,000 to 300,000), the vaccination can cause yellow fever vaccine–associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5% of cases.

The Yellow Fever Initiative, launched by WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI Alliance, and governmental organizations in Europe and Africa. According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected.

In March 2017, WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil.

Currently, no vaccine against relapsing fever is available, but research continues. Developing a vaccine is very difficult because the spirochetes avoid the immune response of the infected person (or animal) through antigenic variation. Essentially, the pathogen stays one step ahead of antibodies by changing its surface proteins. These surface proteins, lipoproteins called variable major proteins, have only 30–70% of their amino acid sequences in common, which is sufficient to create a new antigenic "identity" for the organism. Antibodies in the blood that are binding to and clearing spirochetes expressing the old proteins do not recognize spirochetes expressing the new ones. Antigenic variation is common among pathogenic organisms. These include the agents of malaria, gonorrhea, and sleeping sickness. Important questions about antigenic variation are also relevant for such research areas as developing a vaccine against HIV and predicting the next influenza pandemic.

Protection is offered by Q-Vax, a whole-cell, inactivated vaccine developed by an Australian vaccine manufacturing company, CSL Limited. The intradermal vaccination is composed of killed "C. burnetii" organisms. Skin and blood tests should be done before vaccination to identify pre-existing immunity, because vaccinating people who already have an immunity can result in a severe local reaction. After a single dose of vaccine, protective immunity lasts for many years. Revaccination is not generally required. Annual screening is typically recommended.

In 2001, Australia introduced a national Q fever vaccination program for people working in “at risk” occupations. Vaccinated or previously exposed people may have their status recorded on the Australian Q Fever Register, which may be a condition of employment in the meat processing industry. An earlier killed vaccine had been developed in the Soviet Union, but its side effects prevented its licensing abroad.

Preliminary results suggest vaccination of animals may be a method of control. Published trials proved that use of a registered phase vaccine (Coxevac) on infected farms is a tool of major interest to manage or prevent early or late abortion, repeat breeding, anoestrus, silent oestrus, metritis, and decreases in milk yield when "C. burnetii" is the major cause of these problems.