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 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 Although considered the gold standard, this method lacks sensitivity and has been replaced by PCR in many settings.

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.

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).

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.

The CDC states that PCR testing from a single blood draw is not sufficiently sensitive for "B." "henselae" testing, and can result in high false negative rates due to a small sample volume and levels below the limit of molecular detection.

"Bartonella" spp. are fastidious, slow-growing bacteria that are difficult to grow using traditional solid agar plate culture methods due to complex nutritional requirements and potentially a low number of circulating bacteria. This conventional method of culturing "Bartonella" spp. from blood inoculates plated directly onto solid agar plates requires an extended incubation period of 21 days due to the slow growth rate.

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

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.

"Bartonella" growth rates improve when cultured in an enrichment inoculation step in a liquid insect-based medium such as "Bartonella" α-Proteobacteria Growth Medium (BAPGM) or Schneider’s Drosophila-based insect powder medium. Several studies have optimized the growing conditions of "Bartonella" spp. cultures in these liquid media, with no change in bacterial protein expressions or host interactions "in vitro". Insect-based liquid media supports the growth and co-culturing of at least seven "Bartonella" species, reduces bacterial culturing time and facilitates PCR detection and isolation of "Bartonella" spp. from animal and patient samples. Research shows that DNA may be detected following direct extraction from blood samples and become negative following enrichment culture, thus PCR is recommended after direct sample extraction and also following incubation in enrichment culture. Several studies have successfully optimized sensitivity and specificity by using PCR amplification (pre-enrichment PCR) and enrichment culturing of blood draw samples, followed by PCR (post-enrichment PCR) and DNA sequence identification.

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.

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 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".

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.

Diagnosis is achieved most commonly by serologic testing of the blood for the presence of antibodies against the ehrlichia organism. Many veterinarians routinely test for the disease, especially in enzootic areas. During the acute phase of infection, the test can be falsely negative because the body will not have had time to make antibodies to the infection. As such, the test should be repeated. A PCR (polymerase chain reaction) test can be performed during this stage to detect genetic material of the bacteria. The PCR test is more likely to yield a negative result during the subclinical and chronic disease phases. In addition, blood tests may show abnormalities in the numbers of red blood cells, white blood cells, and most commonly platelets, if the disease is present. Uncommonly, a diagnosis can be made by looking under a microscope at a blood smear for the presence of the "ehrlichia" morulae, which sometimes can be seen as intracytoplasmic inclusion bodies within a white blood cell.

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

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.

The prognosis is good for dogs with acute ehrlichiosis. For dogs that have reached the chronic stage of the disease, the prognosis is guarded. When bone marrow suppression occurs and there are low levels of blood cells, the animal may not respond to treatment.

Antiviral drugs, that target infections with RRV. Patients are usually managed with simple analgesics, anti-inflammatories, anti-pyretics and rest while the illness runs its course.

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.

Several forms of laboratory testing for Lyme disease are available, some of which have not been adequately validated. The most widely used tests are serologies, which measure levels of specific antibodies in a patient's blood. These tests may be negative in early infection as the body may not have produced a significant quantity of antibodies, but they are considered a reliable aid in the diagnosis of later stages of Lyme disease. Serologic tests for Lyme disease are of limited use in people lacking objective signs of Lyme disease because of false positive results and cost.

The serological laboratory tests most widely available and employed are the Western blot and ELISA. A two-tiered protocol is recommended by the Centers for Disease Control and Prevention: the sensitive ELISA test is performed first, and if it is positive or equivocal, then the more specific Western blot is run. The reliability of testing in diagnosis remains controversial. Studies show the Western blot IgM has a specificity of 94–96% for people with clinical symptoms of early Lyme disease. The initial ELISA test has a sensitivity of about 70%, and in two-tiered testing, the overall sensitivity is only 64%, although this rises to 100% in the subset of people with disseminated symptoms, such as arthritis.

Erroneous test results have been widely reported in both early and late stages of the disease, and can be caused by several factors, including antibody cross-reactions from other infections, including Epstein–Barr virus and cytomegalovirus, as well as herpes simplex virus. The overall rate of false positives is low, only about 1 to 3%, in comparison to a false-negative rate of up to 36% in the early stages of infection using two-tiered testing.

Polymerase chain reaction (PCR) tests for Lyme disease have also been developed to detect the genetic material (DNA) of the Lyme disease spirochete. PCR tests are susceptible to false positive results from poor laboratory technique. Even when properly performed, PCR often shows false negative results with blood and cerebrospinal fluid specimens. Hence, PCR is not widely performed for diagnosis of Lyme disease, but it may have a role in the diagnosis of Lyme arthritis because it is a highly sensitive way of detecting "ospA" DNA in synovial fluid.

Culture or PCR are the current means for detecting the presence of the organism, as serologic studies only test for antibodies of "Borrelia". OspA antigens, shedded by live Borrelia bacteria into urine, are a promising technique being studied. The use of nanotrap particles for their detection is being looked at and the OspA has been linked to active symptoms of Lyme. High titers of either immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies to "Borrelia" antigens indicate disease, but lower titers can be misleading, because the IgM antibodies may remain after the initial infection, and IgG antibodies may remain for years.

Western blot, ELISA, and PCR can be performed by either blood test via venipuncture or cerebrospinal fluid (CSF) via lumbar puncture. Though lumbar puncture is more definitive of diagnosis, antigen capture in the CSF is much more elusive; reportedly, CSF yields positive results in only 10–30% of affected individuals cultured. The diagnosis of neurologic infection by "Borrelia" should not be excluded solely on the basis of normal routine CSF or negative CSF antibody analyses.

New techniques for clinical testing of "Borrelia" infection have been developed, such as LTT-MELISA, although the results of studies are contradictory. The first peer reviewed study assessing the diagnostic sensitivity and specificity of the test was presented in 2012 and demonstrated potential for LTT to become a supportive diagnostic tool. In 2014, research of LTT-MELISA concluded that it is "sensible" to include the LTT test in the diagnostic protocol for putative European-acquired Lyme borreliosis infections. Other diagnostic techniques, such as focus floating microscopy, are under investigation. New research indicates chemokine CXCL13 may also be a possible marker for neuroborreliosis.

Some laboratories offer Lyme disease testing using assays whose accuracy and clinical usefulness have not been adequately established. These tests include urine antigen tests, PCR tests on urine, immunofluorescent staining for cell-wall-deficient forms of "B. burgdorferi", and lymphocyte transformation tests. The CDC does not recommend these tests, and stated their use is "of great concern and is strongly discouraged".

A spotted fever is a type of tick-borne disease which presents on the skin. They are all caused by bacteria of the genus "Rickettsia". Typhus is a group of similar diseases also caused by "Rickettsia" bacteria, but spotted fevers and typhus are different clinical entities.

The phrase apparently originated in Spain in the seventeenth century and was ‘loosely applied in England to typhus or any fever involving petechial eruptions.’ During the seventeenth and eighteenth centuries, it was thought to be ‘“cousin-germane” to and herald of the bubonic plague’, a disease which periodically afflicted the city of London and its environs during the sixteenth and seventeenth centuries, most notably during the Great Plague of 1665.

Types of spotted fevers include:

- Mediterranean spotted fever

- Rocky Mountain spotted fever

- Queensland tick typhus

- Helvetica Spotted fever

Neuroimaging is controversial in whether it provides specific patterns unique to neuroborreliosis, but may aid in differential diagnosis and in understanding the pathophysiology of the disease. Though controversial, some evidence shows certain neuroimaging tests can provide data that are helpful in the diagnosis of a patient. Magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) are two of the tests that can identify abnormalities in the brain of a patient affected with this disease. Neuroimaging findings in an MRI include lesions in the periventricular white matter, as well as enlarged ventricles and cortical atrophy. The findings are considered somewhat unexceptional because the lesions have been found to be reversible following antibiotic treatment. Images produced using SPECT show numerous areas where an insufficient amount of blood is being delivered the cortex and subcortical white matter. However, SPECT images are known to be nonspecific because they show a heterogeneous pattern in the imaging. The abnormalities seen in the SPECT images are very similar to those seen in people with cerebral vacuities and Creutzfeldt–Jakob disease, which makes them questionable.

Definitive diagnosis is usually made at a reference laboratory with advanced biocontainment capabilities. The findings of laboratory investigation vary somewhat between the viruses but in general there is a decrease in the total white cell count (particularly the lymphocytes), a decrease in the platelet count, an increase in the blood serum liver enzymes, and reduced blood clotting ability measured as an increase in both the prothrombin (PT) and activated partial thromboplastin times (PTT). The hematocrit may be elevated. The serum urea and creatine may be raised but this is dependent on the hydration status of the patient. The bleeding time tends to be prolonged.