Fever in the Human Immunodeficiency Virus (HIV)Patient

OVERVIEW: What every practitioner needs to know

Are you sure your patient has human immunodeficiency virus (HIV) infection with fever? What should you expect to find?

Some patients may report the presence of fever as part of their condition without having verified its presence objectively. Such subjective reports need to be verified by measurement of temperature in the absence of antipyretic therapy before undertaking an extensive evaluation as to the cause of fever in a human immunodeficiency virus (HIV)-infected patient. For most clinical purposes, fever can be defined as the elevation of body temperature above 38.3°C. Once the presence of fever has been verified, the patient’s history, physical examination, and screening laboratory results may suggest an etiology and identify subsequent laboratory testing and imaging studies to be pursued.

In general, the presence of fever in most HIV-infected patients should prompt the same considerations as the presence of fever in a normal host. Fever is a sign of an underlying disorder and is not a disease in and of itself. Treatment of fever is almost never essential, and the use of antipyretic therapy should be applied thoughtfully and not as a matter of course. Suppressing fever with antipyretics may mean the loss of an important indicator of disease activity or response to therapy. The primary response to fever should be to seek its cause and treat accordingly. Specific treatment of the underlying cause generally results in prompt resolution of the fever.

When assessing a febrile HIV-infected person, it quickly becomes clear that not all HIV-positive patients are comparable. Fever in an HIV-infected patient who has a very low cluster of differentiation (CD)4 count and ongoing HIV replication is a much more concerning situation than fever in an HIV-infected patient with a normal CD4 count and sustained HIV suppression. The latter is essentially evaluation of fever in a normal host, whereas the former is the more urgent evaluation of fever in the immunocompromised host.

Before embarking on an extensive diagnostic evaluation as to the cause of fever, it is important to determine the current status of the febrile patient’s HIV infection.

• If the patient’s HIV status is already established by recent follow-up and ongoing management of his/her HIV infection, then previous measures of the CD4 count and HIV viral load are likely available. Reviewing the most recent viral load and CD4 count, measuring the degree of immunosuppression that has previously been present (as represented by the patient’s CD4 nadir), and determining the likelihood that HIV suppression is ongoing all help to determine the likely range of causes of fever.

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• The information obtained from a careful history of the present illness, including any significant recent exposure and/or travel, is often the key to diagnosis. When combined with the results of the physical examination and initial laboratory studies, such as a complete blood count (CBC), a metabolic profile (that includes hepatic enzymes), a urinalysis, and a chest X-ray, the patient history can be of great value in determining the cause of fever and suggesting initial treatment.

• Current symptoms, including localizing symptoms, should guide the choice of additional testing. For example, a patient with fever and flank pain should have testing to determine if a systemic urinary tract infection is present. A patient with a low CD4 count who presents with progressive dyspnea, a nonproductive cough, and hypoxia should have evaluation for Pneumocystis pneumonia (PCP). A patient with fever, loose stools, abdominal pain, and recent antimicrobial therapy should be assessed for Clostridium difficile colitis. Equally important is the concept of not doing tests for which there is no historical information, physical examination findings, or laboratory clues to suggest pathology.

• If an infectious cause of fever is not apparent, consider noninfectious fever. This may be particularly true if fever is persistent and no diagnosis is made in the initial period of evaluation. If no evidence of infection is apparent, other causes of fever may include:

  Malignancy (especially lymphoma)

  Autoimmune disorders (generally uncommon in HIV-infected persons)

  Drug fever—in addition to such typical causes of drug fever as phenytoin, HIV-specific causes, such as the abacavir (ABC) hypersensitivity syndrome, should be considered in appropriate circumstances. The ABC hypersensitivity syndrome can be largely avoided by prescreening patients for the presence of the human leukocyte antigen (HLA) B-5701, since the vast majority of cases occur in persons who are HLA-B5701-positive. Other antiretroviral drugs, particularly nonnucleoside reverse transcriptase inhibitors (NNRTIs), particularly nevirapine, have been associated with febrile reactions, sometimes accompanied by severe hepatic inflammation. Trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used for prevention of PCP and can cause fever if sulfa allergy is present, as can sulfadiazine, used to treat toxoplasmosis. Drug fever is a diagnosis of exclusion after other causes have been sought and not found.

  Factitious fever (uncommon, but not unheard of)

• Special circumstances

  Fever during acute HIV infection—fever is the most common symptom/sign in patients with acute HIV infection. In patients at risk for acute HIV infection, the presence of fever should lead to diagnostic testing to include HIV ribonucleic acid testing and/or nucleic acid amplification testing.

  Fever in hospitalized HIV-infected patients: Patients hospitalized with intravenous (IV) catheters or indwelling urinary catheters are at risk for hospital-acquired infections and should have appropriate evaluations to assess for these conditions.

  Fever in IV drug users: Most HIV-infected persons who are IV drug users are at considerable risk for hepatitis C virus (HCV) infection and also for cellulitis, septic thrombophlebitis, and bacterial endocarditis. Acute HCV infection is usually asymptomatic, but bacterial endocarditis is invariably symptomatic with fever being a common finding.

  Fever during IRIS (relationship to starting antiretroviral therapy (ART)): A recently recognized finding is the entity known as the immune reconstitution inflammatory syndrome (IRIS). Typically, this occurs in HIV-infected patients who have experienced considerable deterioration of immune function before initiating ART. Once ART has been started and the virus is controlled, the recovery of CD4 cells may result in immune reconstitution and restoration of the ability to generate inflammatory reactions at sites where pathogens have accumulated. These inflammatory changes produce localized pain and swelling and the release of cytokines and other mediators of fever. Thus, persons who may have been relatively asymptomatic develop a febrile illness with localizing symptoms related to inflammation of infected tissues. This can be challenging to distinguish from a primary infection at the site in question.

How did the patient develop HIV with fever? What was the primary source from which the infection spread?

Relative to HIV-uninfected persons, those with HIV infection are at increased risk of diseases causing fever, primarily because HIV causes defects in T-cell function, as well as dysregulation of humoral immunity, particularly in patients with more advanced HIV infection. As the degree of HIV-induced immunosuppression progresses, the range of potential causes of fever expands. Each decrement in CD4 lymphocytes is associated with increased risk of infectious complications, including infection with additional pathogens (see Figure 1).

Figure 1.

As is the case with undiagnosed fever in general, the most common causes of fever in HIV-infected persons are an infectious agent, a neoplasm, a connective tissue disorder, or some other non-infectious cause. As noted, fever itself is not a diagnosis but is a sign of some other underlying condition. An aggressive pursuit of the cause of fever is essential to proper management of febrile HIV-infected patients, particularly those with low CD4 counts and those with significant symptoms. In highly immunocompromised HIV-infected patients, identifying the cause of fever can be life-saving.

Which individuals are of greater risk of developing HIV with fever?

Risk of fever parallels the decline of CD4 cells. Those with the lowest CD4 counts have the greatest risk of HIV-associated complications, many of which cause fever (see Figure 1). The risk of developing a complication that engenders fever is enhanced if HIV replication is not suppressed.

What laboratory studies should you order and what should you expect to find?

The first step is to verify the presence of fever. In general, body temperature is lowest in the morning and rises gradually during the day, peaking in early evening. Fever represents a physiological elevation of body temperature, thus, in the absence of anti-pyretic drugs, fever is superimposed on this diurnal variation in temperature. Most patients will experience a peak in fever in the early evening, and fever tends to abate by the morning. This diurnal variation in temperature (and fever) is thought to be modulated via cortisol secretion. Once fever has been documented, assessment should be undertaken based on the patient’s presenting symptoms and the reported history and physical examination findings.

In most patients with undiagnosed fever, blood cultures should be part of the initial evaluation. It is critically important to do at least two sets of blood cultures before antimicrobial therapy is initiated. Clues from the history and physical examination are usually very important in deciding what other specimens are appropriate. For example, a febrile patient with flank pain and symptoms of a urinary tract infection should have a clean catch urine specimen collected for urinalysis and culture, whereas an HIV-infected person recently returning from international travel with fever and diarrhea should have stool specimens submitted for culture of enteric pathogens and microscopic examination for ova and parasites.

The approach to the evaluation of fever in HIV-infected patients should be characterized by thoughtful and directed laboratory studies, rather than by undifferentiated ordering of laboratory and microbiology testing. A patient who recently received antimicrobial therapy now presenting with loose bowel movements and abdominal discomfort should have stool specimens checked for evidence of C. difficile toxin, whereas a febrile patient with no pulmonary symptoms should not have sputum examination performed as part of the evaluation unless there is some indication that the lungs might be the site of infection or neoplasm as the source of fever. Synthesis of data from the patient history, including such things as degree of immunosuppression and recent travel history, from the presenting symptoms, which may help localize the site of tissue abnormality, and from results of any preliminary testing (i.e., CBC, liver transaminase levels, chest X-ray) often suggest specific additional testing which may clarify the diagnosis.

What imaging studies will be helpful in making or excluding the diagnosis of HIV with fever?

The type of imaging will often be suggested by the presentation of the patient along with the status of his/her HIV infection.

• An HIV-infected patient with a CD4 count less than 200 cells/mm³ who presents with dyspnea, non-productive cough, and hypoxia almost certainly has Pneumocystis pneumonia (PCP) and should have a chest X-ray to evaluate.

• A similar patient presenting with headache and altered mental status should have a brain CT scan or MRI to assess for toxoplasmosis, brain abscess, CNS lymphoma, and other mass lesions. Depending on the findings, examination of cerebrospinal fluid should be done in such a patient to assess for meningitis.

• A patient with fever, abdominal pain, and weight loss often benefits from abdominal imaging to investigate tissues not easily assessed by physical examination. Such a scan may reveal intra-abdominal lymphadenopathy suggestive of lymphoma or infiltrative disease caused by Mycobacterium avium complex (MAC) infection.

• An intravenous drug user with undifferentiated fever should have echocardiography to assess for vegetation on heart valves indicative of endocarditis.

As with laboratory testing, imaging studies should be based on thoughtful consideration of the patient’s symptoms, recent history, and the results of the initial assessment, including determination of HIV status (CD4 count and HIV RNA viral load). Undifferentiated ordering of imaging studies may result in misleading findings that require additional testing for clarification, wasting resources, delaying correct diagnosis, and exposing patients to unnecessary risk.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has HIV with fever, what therapies should you initiate immediately?

It is almost reflexive in most medical settings to treat fever with antipyretic therapy, largely based on the notion that fever is by its very nature injurious. Conversely, there is some evidence that elevated body temperature in response to infection represents an adaptive response, favoring certain immunologic functions through elevated body temperatures. And, although the presence of fever does cause increased metabolic demand, for most persons, these demands are relatively modest and not deleterious.

One major concern with using antipyretic intervention is that it may mask the course of fever and make it more difficult to assess the response to presumptive antimicrobial therapy or to identify spontaneous resolution of the febrile condition. If antipyretics seem advisable, they should be administered on a schedule that reflects their pharmacologic effect rather than to give them on an “as needed” basis, which often subjects febrile patients to large temperature swings as the effect of the antipyretics waxes and wanes.

The preferred treatment of fever is proper treatment of the underlying cause. Thus, fever associated with a systemic urinary tract infection will subside once appropriate antimicrobials sterilize the urinary tract and remove the impetus to fever. Making the right diagnosis and treating with effective antimicrobial agents is the optimal treatment of most infectious causes of fever.

Some patients at high risk of complications of infection or who have infection present in critical anatomic locations (e.g., presumed bacterial meningitis or endocarditis) benefit from presumptive therapy based on the site of the apparent infection and consideration of the potential pathogens at that site. When such a management plan is implemented, it is critically important to obtain sufficient specimens for the microbiology laboratory to maximize the likelihood that an etiologic diagnosis will be possible. After implementing an antimicrobial treatment intervention, the patient must be re-evaluated at frequent intervals to assess the response and make judgments as to the appropriateness of the response. If the response is inadequate, the diagnostic approach should be revisited and the components of the treatment regimen reconsidered.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Initiation of a presumptive treatment regimen requires very close monitoring to determine response. The choice of treatment is determined by the proposed diagnosis, by awareness of the organisms most likely to cause disease at the presumed site of infection, and by knowledge of the antimicrobial susceptibility of pathogens in the area in which the infection is thought to have been acquired. Ideally, specimens collected from the presumed site of infection are subsequently found to harbor the causative organism, and therapy specific to that pathogen can be applied. In the absence of a microbiologic diagnosis, assessment of the treatment response of the fever, the overall patient status, and the abnormalities identified pretreatment, such as leukocytosis, cerebrospinal fluid (CSF) pleocytosis, and pulmonary infiltrates, suggest the appropriateness of the presumptive treatment regimen.

There are many guidelines and handbooks that suggest specific antimicrobial regimens for specific types of infections, and, in the absence of more patient-specific information, following such recommendations is reasonable. It is also important to ensure the patient is not allergic to any of the presumptive antimicrobial drugs are selected for presumptive treatment.

An underappreciated management strategy is that of careful observation, rather than hasty, ill-conceived intervention. This approach, which has been termed, “masterly inactivity,” involves close monitoring of the patient while the diagnosis is uncertain and may be reasonable when the patient’s clinical status is stable, the underlying degree of immunosuppression is modest, and the presumed site of infection is not a critically important organ. In some situations, it may be preferable to avoid antibacterial therapy (e.g., a patient with recent severe C. difficile colitis may be at risk for recurrence if antimicrobials are administered). A careful risk-benefit analysis should be central to the decision to start treatment. Aggressive pursuit of an accurate microbiologic diagnosis should continue and willingness to initiate presumptive therapy if clinical deterioration is observed are important features of this approach.

2. Next list other key therapeutic modalities.

In most patients, fever is not a condition that produces meaningful morbidity or complications by itself. It is often best left untreated aside from the treatment of the underlying cause. In patients with medical conditions in which the increased metabolic demand associated with fever is problematic (e.g., patients with limited cardiac reserve, perhaps due to prior myocardial infarction or valvular heart disease), suppression of fever with “round-the-clock” antipyretic therapy (i.e., acetaminophen, aspirin, NSAIDs) may be of benefit.

If patients complain of feeling particularly unwell when febrile, it is also reasonable to administer antipyretics to improve the patient’s sense of well-being. In reality, much of the unpleasantness of fever is concentrated in the periods when increased body temperature is being generated (i.e., chills, muscle contractions, feeling cold) and when fever abates (i.e., flushed sensation, diffuse perspiration). These symptoms are often exacerbated by the use of antipyretics, particularly when administered via “as needed” order.

Because fever can be associated with increased fluid requirements, patients who are otherwise healthy should be encouraged to drink plentiful amounts of water or, alternatively, intravenous hydration can be provided.

With some diagnoses associated with fever, other therapies are appropriate (e.g., repeated lumbar puncture for relief of elevated cerebrospinal fluid (CSF) pressure in patients with cryptococcal meningitis), but these are not directed primarily at fever as the problem.

What complications could arise as a consequence of HIV with fever?

What should you tell the family about the patient's prognosis?

Prognosis in patients with fever is a function of the underlying cause of the fever. The fever itself is not the determinant of outcome. If antipyretics are not used, the family should be informed as to why this is the strategy, since “fever-phobia” is widespread and most non-physicians are convinced that failure to suppress fever equates with poor care.

Add what-if scenarios here:

If apparently appropriate treatment fails to reduce fever despite clinical improvement, non-infectious causes of fever should be sought, including drug fever related to the antimicrobial regimen. Beta lactam antibiotics are well-described causes of drug fever. In addition, lymphoma can be misdiagnosed as infection, and antimicrobial therapy obviously has no effect on neoplastic causes of fever. Failure of the fever to respond to presumptive therapy should prompt re-initiation of the diagnostic evaluation.

How do you contract HIV with fever and how frequent is this disease?

Fever is one of the most common findings of disease and is the result of changes in the hypothalamus that change the body’s temperature set-point. Most changes result from substances (termed cytokines) elaborated by cells in the body, including white blood cells. It is thought that external factors, such as bacterial pathogens, serve as exogenous pyrogens to drive the fever response. The mediator of this phenomenon is the host response to the presence of these exogenous pyrogens (elaboration of cytokines, which result in elevated body temperature by means of their effect on the hypothalamus). There are many cytokines thought to produce fever, all of which are collectively termed endogenous pyrogens. The list includes interleukin-1 (IL-1), tumor necrosis factor (TNF), IL-6, and interferon.

In most instances, the resetting of the temperature set-point is superimposed on the normal diurnal variation in temperature. As a result, body temperature (and fever) tends to be the highest in the early evening and diminishes overnight, such that the lowest body temperature, which corresponds to the peak level of serum cortisol, occurs in the early morning.

What pathogens are responsible for this disease?

Virtually any virus, bacterium, parasite, or fungus that results in human infection can also be associated with fever. Compilations of data on the diagnosis of fever in both HIV-infected and uninfected patients yields a list of some of the more common pathogens seen with HIV-positive patients. A comprehensive list is beyond the scope of this publication, but the following represent pathogens that may be particularly relevant for HIV-infected persons.

Bacteria

Staph aureus: HIV-infected persons have higher rates of Staph aureus colonization. Cutaneous infection is common and can lead to bacteremia.

Clostridium difficile infection: This disorder almost always results from prior antimicrobial therapy that allows overgrowth of Clostridium difficile in the gastrointestinal (GI) tract, leading to elaboration of toxins that cause inflammation of the colon. Fever is common with C. difficile colitis, which may be recurrent and persistent.

Bartonella species: B. henselae and B. quintana can cause bacillary angiomatosis, especially in those with CD4 counts less than 50 cells/mm³. Lesions are vascular papules that can evolve to nodules and mimic Kaposi sarcoma. Fever is often a manifestation of Bartonella infection in HIV-infected patients.

Neisseria gonorrhoeae: Disseminated gonococcal infection (DGI) is associated with fever and peripheral pustules and may include large joint arthritis, especially the knee.

Treponema pallidum: HIV-positive patients, especially in men who have sex with men (MSM), have relatively high rates of syphilis. Secondary syphilis is commonly associated with rash involving palms and soles and is typically a febrile illness.

Streptococcus pneumonia: Rates of disseminated bacteremic pneumococcal infection among AIDS patients are 100-fold higher than in HIV-uninfected persons. The availability of effective antiretroviral therapy has greatly diminished the frequency of systemic pneumococcal infection.

Salmonella species are a relatively common cause of abdominal pain and fever (so-called enteric fever) in AIDS patients. AIDS patients with Salmonella infection are frequently bacteremic. HIV-infected febrile travelers are a substantial risk population for this diagnosis.

Mycobacteria including Tuberculosis

Mycobacterial infections are particularly common in HIV-infected patients. Those with very low CD4 counts have high risk of systemic mycobacterium avium complex (MAC) infection, which may present with fever and abdominal pain as primary symptoms. Worldwide, Mycobacterium tuberculosis is a very frequent diagnosis among HIV-positive patients. Other so-called “atypical mycobacterium” may also cause febrile illness in HIV-infected persons, particularly those with low CD4 counts.

Fungi

By far the most common fungal cause of fever in HIV-infected patients is Pneumocystis jirovecii (formerly termed Pneumocystis carinii). PCP remains the leading opportunistic infection among HIV-infected patients and typically presents with sub-acute pulmonary symptoms, including non-productive cough, dyspnea on exertion, and hypoxia. Chest X-ray usually demonstrates bilateral interstitial infiltrates, although the findings can be quite variable to include a normal chest X-ray. Fever is almost always present.

After pneumocystis infection, the most common fungal cause of fever in HIV-infected patients is Cryptococcus neoformans. Often presenting as meningitis, it can also cause pulmonary disease, skin lesions, and a febrile systemic illness.

Histoplasmosis is not uncommon in the Mississippi River valley area of the United States and also occurs in other areas of the world, including Central and South America, parts of Africa, and Southeast Asia. Immunocompromised HIV-infected patients are prone to severe systemic disseminated infection with fever as a prominent symptom.

Blastomycosis is an endemic fungal infection that may present with fever accompanying central nervous system (CNS), pulmonary, and cutaneous manifestations. It may also cause severe disseminated disease in immunocompromised HIV-infected patients.

Coccidioidomycosis is found in the southwestern United States, much of Central America, and parts of South America, including Argentina. In highly endemic areas, it occurs with some frequency in AIDS patients, often with fever. It can cause pulmonary disease, bone infection, and CNS symptoms/chronic meningitis.

Candidiasis is most often a localized infection of the pharynx but can also extend into the esophagus, and, in such cases, fever may be a presenting symptom along with dysphagia and odynophagia.

Other uncommon fungal causes of febrile illness in immunocompromised HIV-infected patients include Sporotrichosis and Penicillium marneffei infection.

Viruses

Human immunodeficiency virus (HIV): Fever is the most common symptom seen in persons with acute HIV infection, often accompanied by rash, fatigue, GI symptoms, malaise, sore throat, and weight loss. Headache, lymphadenopathy, myalgias, and arthralgias are also relatively common in patients with acute HIV infection. In contrast to the frequency of fever during acute HIV infection, fever is not usually present during untreated chronic HIV infection. Nonetheless, in some immune suppressed febrile patients, extensive investigations may not yield a diagnosis explaining fever. In such cases, by exclusion, fever has been attributed to chronic HIV infection, but such attribution remains speculative.

Herpes virus infections are common in HIV-infected persons and can be associated with significant fever.

• HSV: Primary genital herpes infection can be associated with systemic symptoms, including fever. Recurrent genital herpes is not generally a febrile illness.

• Varicella zoster virus (VZV): Reactivation of VZV from dorsal nerve root ganglia is more common among HIV-infected persons with lower CD4 counts. VZV causes recurrent infection (shingles) in a dermatomal distribution, the risk of which is related to the degree of immunosuppression (higher risk with lower CD4 count).

• Cytomegalovirus (CMV): In HIV-infected patients, CMV is a well-recognized cause of gastrointestinal disease (most often colitis, but sometimes esophagitis) and eye disease (retinitis). CMV retinitis is very uncommon in persons with CD4 counts greater than 100 cells/mm³, and GI CMV is also most often seen in HIV-positive patients with lower CD4 counts. CMV viremia is present in a substantial percentage of immune suppressed patients; if such patients have fever, the causal link between CMV and fever remains uncertain.

Parvovirus B19 causes fever, arthritis, and sometimes rash in HIV-infected persons. It can also be a cause of severe anemia, but only in the context of severe immune suppression

Hepatitis viruses: Acute infection with hepatitis A and B can be associated with fever, whereas most cases of acute hepatitis C are asymptomatic, as shown in a study of recipients of HCV-contaminated blood transfusions. In a study of sexually acquired acute HCV infection, 18 out of 21 cases were asymptomatic.

Influenza is a common cause of fever in HIV-infected patients and should be strongly considered during epidemic periods.

Parasites

Cryptosporidium is a self-limited illness in most immunocompetent patients but may produce prolonged diarrheal disease in HIV-infected persons with low CD4 counts. Low grade fever as part of the systemic signs and symptoms of cryptosporidiosis is common.

Toxoplasmosis is a major cause of brain abscesses in HIV-infected persons with advanced immunosuppression. Distinguishing toxoplasmosis from CNS lymphoma can be challenging, and biopsy is sometimes required to verify the diagnosis. Although both conditions can be associated with fever, most patients with CNS toxoplasmosis are afebrile.

Leishmaniasis is an infection that can be cutaneous or systemic, depending, for the most part, on its geographic origin. Visceral leishmaniasis can be a significant cause of fever in endemic areas but is not found indigenously in the United States.

What other clinical manifestations may help me to diagnose and manage HIV with fever?

Certain collections of signs and symptoms in HIV-infected persons may be of value in considering the cause of fever.

Fever and rash

Skin rash is very common among HIV-infected patients, and fever plus rash can represent the presence of significant infection. Early biopsy and examination of tissues for the presence of infectious pathogens is often a critically important step in defining the cause of fever. Tissues should be cultured for fungi and mycobacteria in virtually all cases and for viruses when suspicion is high. Among the infections that can be linked to cutaneous abnormalities and fever are:

Staphylococcus aureus: Risk factors for Staph aureus bacteremia in HIV-infected patients include nasal colonization, intravenous (IV) drug use, lymphedema (sometimes a result of Kaposi sarcoma), neutropenia, and indwelling IV catheters.

Methicillin-resistant Staph aureus (MRSA): MRSA is increasingly common among HIV-infected patients. A variety of dermatologic manifestations of S. aureus are seen, including impetigo, folliculitis, cellulitis, skin abscesses and ulcerations, and ecthyma gangrenosum. Antimicrobial therapy and drainage of abscesses is important in reducing the frequency of bacteremia and complications.

Bacillary angiomatosis: Bartonella species can produce vascular skin lesions in HIV-infected patients with low CD4 counts. The organism can spread to visceral tissues and cause bacteremia and fever, being a cause of “fever of unknown origin” in HIV-infected persons.

Sexually acquired infections (STIs): STIs occur with increased frequency in HIV-infected patients. Neisseria gonorrhea can produce pelvic inflammatory disease (PID) in women and disseminated gonococcal infection (DGI) in men and women. Both are associated with fever. DGI may include peripheral pustules, tenosynovitis, as well as large joint infectious arthritis (most often involving the knee). Treponema pallidum is much more common in MSM, and secondary syphilis often presents with fever and a disseminated rash including involvement of the palms and soles.

Mycobacteria can cause cutaneous disease and fever in HIV-infected patients, although this is not common. MAC, Mycobacterium kansasii, and even M. tuberculosis have been noted to cause polymorphic skin lesions and subcutaneous nodules in this setting, and diagnostic biopsies of undifferentiated skin lesions should be cultured for mycobacteria. Mycobacterium hemophilum has been reported in rare instances as a cause of fever and skin lesions in HIV-infected patients with advanced immunosuppression. The lesions may begin as painless papules or nodules and progress to painful erythematous ulcerations. Fever is more common with lymphadenitis or pneumonitis. Biopsy and culture is the appropriate diagnostic strategy.

Viruses: As mentioned previously, varicella zoster, herpes simplex, and parvovirus are viral infections that can cause skin disease and fever in HIV-infected persons.

Fungi: Endemic fungal infections, including Cryptococcus neoformans, Histoplasma capsulatum, Bastomyces dermatitidis, and Coccidioides immitis, all occur with increased frequency in HIV-infected populations. Cutaneous disease is relatively common, and biopsied tissues should be cultured and examined for these pathogens.

• Sporothrix schenckii almost always presents with cutaneous disease, often after direct inoculation.

• Penicillium marneffi infection is most often diagnosed in HIV-infected persons from Southeast Asia, India, or China, particularly in those with very low CD4 counts. It can produce fever and systemic illness characterized by weight loss, respiratory symptoms, anemia, and popular skin lesions.

• Pneumocystis jirovecii is the most common AIDS-defining infection among persons with HIV and can rarely be associated with cutaneous lesions, most often in the area of the external auditory canal area.

Parasites: Leishmania classically causes either cutaneous disease or visceral disease, depending on species and origin of infection. In HIV-infected patients, there can be considerable overlap and leishmaniasis is a relatively common cause of fever in HIV-infected persons in endemic areas.

Fever and drug reactions

Drug reactions appear to occur with increased frequency among HIV-infected persons. They are not uncommonly accompanied by fever, especially the more severe cases. The most common drug to engender rash is trimethoprim-sulfamethoxazole, used to treat or prevent PCP. Other sulfa drugs can also produce rash and fever. Antiretroviral drugs can also cause rash and fever with the most important causes being abacavir and nevirapine, both of which are occasionally associated with life-threatening reactions.

Abacavir hypersensitivity syndrome causes fever, systemic symptoms, respiratory complaints, and GI symptoms, generally progressing over hours to several days, although the pace may vary considerably from patient to patient. The symptoms typically start in the first few weeks after initiating abacavir. This reaction is almost always found in persons who are HLA-B5701-positive, and the frequency of abacavir hypersensitivity syndrome has been greatly diminished by screening patients for HLA-B5701 prior to starting abacavir. Nevirapine has been associated with severe cutaneous and systemic reactions progressing to Stevens Johnson syndrome in some patients, particularly those with higher CD4 counts at the time of nevirapine initiation. The drug is no longer recommended for initiation in patients with CD4 counts greater than 250 cells/mm³ (women) or 400 cells/mm³ (men).

Other drugs can also cause fever in HIV-infected patients. Although classically thought to be seen soon after drug initiation, drug fever can occur even if patients have been on a particular drug for years. In patients with no clear source of fever, particularly if the fever is present in a patient who is otherwise relatively well, drug fever should be suspected. All non-essential drugs should be discontinued and interruption of suspected agents attempted whenever possible. In most instances, fever will subside promptly after the drug is cleared from the body. Drug fever remains a diagnosis of exclusion.

Fever and malignancies in HIV-infected patients

Lymphoma is by far the most common cause of fever among HIV-infected persons who are ultimately found to have malignancy as the source of the fever. Studies of fever of unknown origin (FUO) in HIV-infected patients demonstrate lymphoma to be the only neoplastic disorder commonly identified. Lymphoma accounts for less than 10% of FUO in HIV-infected patients.

Immune reconstitution inflammatory syndrome (IRIS) and fever

Not long after the introduction of combination antiretroviral treatment (cART) into practice, paradoxical responses to treatment of certain patients were noted. In patients with more advanced HIV infection and immunocompromise, the suppression of HIV along with significant increases in CD4 counts sometimes produced symptoms that mimicked opportunistic infection. This appeared to be particularly common in the case of MAC infection in which the restoration of immune function was accompanied by swelling of lymphoid tissues, pain, and fever. Further assessment of this condition led to the conclusion that it was a manifestation of improved immune recognition of microbial pathogens that had infiltrated tissues without previously eliciting an inflammatory response.

Once immune function was restored, the host pathogen interaction led to marked increases in inflammatory mediators and symptomatic worsening. This syndrome, now termed IRIS, has been described for many opportunistic pathogens and should be suspected as the source of fever in patients with strong CD4 responses to cART, particularly if the pretreatment CD4 count is quite low. IRIS is generally self-limited, and continuing treatment with both cART and pathogen-specific antimicrobials is usually the best course to follow. If IRIS symptoms are severe, it may occasionally be necessary to give a course of corticosteroids.

Additional laboratory studies

Laboratory studies for the diagnosis of fever in HIV-infected patients do not generally differ from those in HIV-uninfected patients. When the diagnosis is elusive and the patient fulfills the criteria for fever of unknown origin, other diagnostic modalities may sometimes be of value.

• Bone marrow biopsy can be helpful in cases of salmonella, leishmania, some fungal and mycobacterial infections, and fever due to lymphoma.

• Liver biopsy in patients with undiagnosed fever and abnormal liver enzymes is sometimes helpful in defining an etiologic diagnosis.

• In most cases, other less invasive testing was equally helpful, obviating the need for this invasive test.

More standard imaging studies, including echocardiography, computed tomographic (CT) scans, and magnetic resonance imaging (MRI) scans, have proven very useful in examining tissues difficult to assess by physical examination. Positron emission tomography (PET) scans are used in some instances to attempt to differentiate neoplasm from infection and are often best interpreted in conjunction with CT or MRI scans of the same tissues.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Barat, L, Gunn, J, Steger, K, Perkins, C, Craven, D. “Causes of fever in patients infected with human immunodeficiency virus who were admitted to Boston City Hospital”. Clin Infect Dis. vol. 23. 1996. pp. 320-8. (This source illustrates 220 episodes of fever in HIV-positive patients who were admitted. Most had CD4 counts less than 200 cells/mm3, and bacterial infections, especially pneumonia, were the most common diagnosis.)

Cohen, MS, Shaw, GM, McMichael, AJ, Haynes, BF. “Acute HIV-1 infection”. N Engl J Med. vol. 364. 2011 May 19. pp. 1943-54. (This is a comprehensive and up-to-date review of primary or acute HIV infection, including the pathophysiology and presentation of the disease.)

Davis, C, Shearer, W. “Diagnosis and management of HIV drug hypersensitivity”. J Allergy Clin Immunol. vol. 121. 2008. pp. 826(This is a review of the approach to drug hypersensitivity reactions with a focus on abacavir, nevirapine, TMP-SMX as major causes.)

Diamond, C, Taylor, TH, Aboumrad, T, Anton-Culver, H. “Changes in acquired immunodeficiency syndrome-related non-Hodgkin lymphoma in the era of highly active antiretroviral therapy: incidence, presentation, treatment, and survival”. Cancer. vol. 106. 2006. pp. 128(This source describes non-Hodgkin lymphoma in HIV-positive patients and the influence of current ART on the incidence and outcomes.)

Hot, A, Schmulewitz, L, Viard, JP, Lortholary, O. “Fever of unknown origin in HIV/AIDS patients”. Infect Dis Clin North America. 2007. pp. 1013-32. This source describes HIV-infected patients with FUO and notes its similarity to other groups with FUO. Infection is most often the cause and workup.)

Klein, M, Lu, Y, DelBalso, L, Cote, S, Boivin, G. “Influenzavirus infection is a primary cause of febrile respiratory illness in HIV-infected adults, despite vaccination”. Clin Infect Dis. vol. 45. 2007. pp. 234-40. (Frequency of influenza as a cause of fever and respiratory symptoms was high despite prior vaccination. Providers should be alert to this diagnosis. Illness tended to be mild in those vaccinated.)

Murdoch, D, Venter, W, Van Rie, A, Feldman, C. “Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options”. AIDS Res Ther. vol. 4. 2007. pp. 9(This is a nice review of the various manifestations of IRIS, its presumed pathophysiology, and management guidelines for the various pathogens causing IRIS.)

Ratnam, I, Chiu, C, Kandala, n, Easterbrook, P. “Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort”. Clin Infect Dis. vol. 42. 2006. pp. 418(This paper reviews data on 44 cases of IRIS occurring among 199 patients starting combination antiretroviral therapy. Predictors of IRIS are identified, and management strategies are proposed.)

Schacker, T, Collier, AC, Hughes, J, Shea, T, Corey, L. “Clinical and epidemiologic features of primary HIV infection”. Ann Intern Med. vol. 125. 1996. pp. 257(This is a compilation of data on 46 adult patients diagnosed with acute HIV infection that describes clinical presentation and laboratory findings, as well as diagnostic approach.)

DRG CODES and expected length of stay

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