In endemic areas, diagnosis is generally made on clinical grounds alone. However, overshadowing of the diagnosis is quite often as the clinical symptoms overlap with other infectious diseases such as dengue fever, paratyphoid, and pyrexia of unknown origin (PUO). If the eschar can be identified, it is quite diagnostic of scrub typhus, but this is very unreliable in the native population who have dark skin, and moreover, the site of eschar which is usually where the mite bites is often located in covered areas. Unless it is actively searched for, the eschar most likely would be missed. History of mite bite is often absent since the bite does not inflict pain and the mites are almost too small to be seen by the naked eye. Usually, scrub typhus is often labelled as PUO in remote endemic areas, since blood culture is often negative, yet it can be treated effectively with chloramphenicol. Where doubt exists, the diagnosis may be confirmed by a laboratory test such as serology. Again, this is often unavailable in most endemic areas, since the serological test involved is not included in the routine screening tests for PUO, especially in Burma (Myanmar).

The choice of laboratory test is not straightforward, and all currently available tests have their limitations. The cheapest and most easily available serological test is the Weil-Felix test, but this is notoriously unreliable. The gold standard is indirect immunofluorescence, but the main limitation of this method is the availability of fluorescent microscopes, which are not often available in resource-poor settings where scrub typhus is endemic. Indirect immunoperoxidase, a modification of the standard IFA method, can be used with a light microscope, and the results of these tests are comparable to those from IFA. Rapid bedside kits have been described that produce a result within one hour, but the availability of these tests is severely limited by their cost. Serological methods are most reliable when a four-fold rise in antibody titre is found. If the patient is from a nonendemic area, then diagnosis can be made from a single acute serum sample. In patients from endemic areas, this is not possible because antibodies may be found in up to 18% of healthy individuals.

Other methods include culture and polymerase chain reaction, but these are not routinely available and the results do not always correlate with serological testing, and are affected by prior antibiotic treatment. The currently available diagnostic methods have been summarised.

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.

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.

The American Public Health Association recommends treatment based upon clinical findings and before culturing confirms the diagnosis. Without treatment, death may occur in 10 to 60 percent of patients with epidemic typhus, with patients over age 60 having the highest risk of death. In the antibiotic era, death is uncommon if doxycycline is given. In one study of 60 hospitalized patients with epidemic typhus, no patient died when given doxycycline or chloramphenicol. Some patients also may need oxygen and intravenous (IV) fluids.

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.

As of 2017 there is no commercially available vaccine. A vaccine has been in development for scrub typhus known as the scrub typhus vaccine.

The disease can be fatal if left untreated, but endemic typhus is highly treatable with antibiotics. Most people recover fully, but death may occur in the elderly, severely disabled or patients with a depressed immune system. The most effective antibiotics include tetracycline and chloramphenicol. In United States, CDC recommends solely doxycycline.

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 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.

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

The infection is treated with antibiotics. Intravenous fluids and oxygen may be needed to stabilize the patient. There is a significant disparity between the untreated mortality and treated mortality rates: 10-60% untreated versus close to 0% treated with antibiotics within 8 days of initial infection. Tetracycline, Chloramphenicol, and doxycycline are commonly used. Infection can also be prevented by vaccination.

Some of the simplest methods of prevention and treatment focus on preventing infestation of body lice. Complete change of clothing, washing the infested clothing in hot water, and in some cases also treating recently used bedsheets all help to prevent typhus by removing potentially infected lice. Clothes also left unworn and unwashed for 7 days also cause both lice and their eggs to die, as they have no access to their human host. Another form of lice prevention requires dusting infested clothing with a powder consisting of 10% DDT, 1% malathion, or 1% permethrin, which kill lice and their eggs.

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.

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.

A combination of clinical signs, symptoms, and laboratory tests can confirm the likelihood of having CTF. Some tests include complement fixation to Colorado tick virus, immunofluorescence for Colorado tick fever, and some other common laboratory findings suggestive of CTF, including leucopenia, thrombocytopenia, and mildly elevated liver enzyme levels.

Detection of viral antibodies on red blood cells is possible.

Rocky Mountain spotted fever can be a very severe illness and patients often require hospitalization. Because "R. rickettsii" infects the cells lining blood vessels throughout the body, severe manifestations of this disease may involve the respiratory system, central nervous system, gastrointestinal system, or kidneys.

Long-term health problems following acute Rocky Mountain spotted fever infection include partial paralysis of the lower extremities, gangrene requiring amputation of fingers, toes, or arms or legs, hearing loss, loss of bowel or bladder control, movement disorders, and language disorders. These complications are most frequent in persons recovering from severe, life-threatening disease, often following lengthy hospitalizations

No rapid laboratory tests are available to diagnose rickettsial diseases early in the course of illness, and serologic assays usually take 10-12 days to become positive. Research is indicating that swabs of eschars may be used for molecular detection of rickettsial infections.

Doxycycline has been used in the treatment of rickettsial infection.

Without treatment, the disease is often fatal. Since the use of antibiotics, case fatalities have decreased from 4–40% to less than 2%.

The drug most commonly used is doxycycline or tetracycline, but chloramphenicol is an alternative. Strains that are resistant to doxycycline and chloramphenicol have been reported in northern Thailand. Rifampicin and azithromycin are alternatives. Azithromycin is an alternative in children and pregnant women with scrub typhus, and when doxycycline resistance is suspected. Ciprofloxacin cannot be used safely in pregnancy and is associated with stillbirths and miscarriage.

Combination therapy with doxycycline and rifampicin is not recommended due to possible antagonism.

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.

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.

Only specialized laboratories can adequately diagnose "Babesia" infection in humans, so "Babesia" infections are considered highly under-reported. It develops in patients who live in or travel to an endemic area or receive a contaminated blood transfusion within the preceding 9 weeks, so this aspect of the medical history is vital. Babesiosis may be suspected when a person with such an exposure history develops persistent fevers and hemolytic anemia. The definitive diagnostic test is the identification of parasites on a Giemsa-stained thin-film blood smear.

So-called "Maltese cross formations" on the blood film are diagnostic (pathognomonic) of babesiosis, since they are not seen in malaria, the primary differential diagnosis. Careful examination of multiple smears may be necessary, since "Babesia" may infect less than 1% of circulating red blood cells, thus be easily overlooked.

Serologic testing for antibodies against "Babesia" (both IgG and IgM) can detect low-level infection in cases with a high clinical suspicion, but negative blood film examinations. Serology is also useful for differentiating babesiosis from malaria in cases where people are at risk for both infections. Since detectable antibody responses require about a week after infection to develop, serologic testing may be falsely negative early in the disease course.

A polymerase chain reaction (PCR) test has been developed for the detection of "Babesia" from the peripheral blood. PCR may be at least as sensitive and specific as blood-film examination in diagnosing babesiosis, though it is also significantly more expensive. Most often, PCR testing is used in conjunction with blood film examination and possibly serologic testing.

Other laboratory findings include decreased numbers of red blood cells and platelets on complete blood count.

In animals, babesiosis is suspected by observation of clinical signs (hemoglobinuria and anemia) in animals in endemic areas. Diagnosis is confirmed by observation of merozoites on thin film blood smear examined at maximum magnification under oil using Romonovski stains (methylene blue and eosin). This is a routine part of the veterinary examination of dogs and ruminants in regions where babesiosis is endemic.

"Babesia canis" and "B. bigemina" are "large "Babesia" species" that form paired merozoites in the erythrocytes, commonly described as resembling "two pears hanging together", rather than the "Maltese cross" of the "small "Babesia" species". Their merozoites are around twice the size of small ones.

Cerebral babesiosis is suspected "in vivo" when neurological signs (often severe) are seen in cattle that are positive for "B. bovis" on blood smear, but this has yet to be proven scientifically. Outspoken red discoloration of the grey matter "post mortem" further strengthens suspicion of cerebral babesiosis. Diagnosis is confirmed "post mortem" by observation of "Babesia"-infected erythrocytes sludged in the cerebral cortical capillaries in a brain smear.

No specific treatment for CTF is yet available. The first action is make sure the tick is fully removed from the skin, then acetaminophen and analgesics can be used to help relieve the fever and pain. Aspirin is not recommended for children, as it has been linked to Reye’s syndrome in some viral illnesses. Salicylates should not be used because of thrombocytopenia, and the rare occurrence of bleeding disorders. People who suspect they have been bitten by a tick or are starting to show signs of CTF should contact their physicians immediately.

Feeding on a human who carries the bacterium infects the louse. "R. prowazekii" grows in the louse's gut and is excreted in its feces. The disease is then transmitted to an uninfected human who scratches the louse bite (which itches) and rubs the feces into the wound. The incubation period is one to two weeks. "R. prowazekii" can remain viable and virulent in the dried louse feces for many days. Typhus will eventually kill the louse, though the disease will remain viable for many weeks in the dead louse.

Epidemic typhus has historically occurred during times of war and deprivation. For example, typhus killed hundreds of thousands of prisoners in Nazi concentration camps during World War II. The deteriorating quality of hygiene in camps such as Auschwitz, Theresienstadt, and Bergen-Belsen created conditions where diseases such as typhus flourished. Situations in the twenty-first century with potential for a typhus epidemic would include refugee camps during a major famine or natural disaster. In the periods between outbreaks, when human to human transmission occurs less often, the flying squirrel serves as a zoonotic reservoir for the "Rickettsia prowazekii" bacterium.

Henrique da Rocha Lima in 1916 then proved that the bacterium "Rickettsia prowazekii" was the agent responsible for typhus; he named it after H. T. Ricketts and Stanislaus von Prowazek, two zoologists who had died from typhus while investigating epidemics. Once these crucial facts were recognized, Rudolf Weigl in 1930 was able to fashion a practical and effective vaccine production method by grinding up the insides of infected lice that had been drinking blood. It was, however, very dangerous to produce, and carried a high likelihood of infection to those who were working on it.

A safer mass-production-ready method using egg yolks was developed by Herald R. Cox in 1938. This vaccine was widely available and used extensively by 1943.

Omsk Hemorrhagic Fever could be diagnosed by isolating virus from blood, or by serologic testing using immunosorbent serological assay. OHF rating of fatality is 0.5–3%. There is no specific treatment for OHF so far but one way to help get rid of OHF is by supportive therapy. Supportive therapy helps maintain hydration and helps to provide precautions for patients with bleeding disorders.

Previous methods of diagnosis included HI, complement fixation, neutralization tests, and injecting the serum of infected individuals into mice. However, new research has introduced more efficient methods to diagnose KFDV. These methods include: nested RT-PCR, TaqMan-based real-time RT-PCR, and immunoglobin M antibodies detection by ELISA. The two methods involving PCR are able to function by attaching a primer to the NS-5 gene which is highly conserved among the genus to which KFDV belongs. The last method allows for the detections of anti-KFDV antibodies in patients.