Complications of human immunodeficiency virus
Complications of human immunodeficiency virus (HIV) infection include a wide array of clinical problems that can affect virtually every organ system. Prior to the advent of highly active antiretroviral therapy (HAART), the majority of complications were comprised of opportunistic illnesses (OIs), which included infections and malignancies. In current times, the spectrum of disease encompasses more non-acquired immune deficiency syndrome (AIDS)-defining cancers, complications of concomitant illnesses, and side effects of HAART.
Side effects of HAART are discussed in another chapter. This chapter will focus on the approach to non-pharmacologic complications of HIV/AIDS by organ system. Please note that this chapter summarizes the approach to the hospitalized patient in the United States (US); should the patient be a recent immigrant, the differential diagnosis may need to broadened based on the area of origin.
HIV-infected individuals commonly present to the hospital setting with shortness of breath, lymphadenopathy, diarrhea, rashes, or general systemic symptoms such as weight loss and fever. The list of differential diagnoses broadens in direct proportion to the degree of immunocompromise as measured by the cluster of differentiation (CD4) count.
While patients with CD4 counts above 200 often present with infections common to immunocompetent hosts, they also have higher rates of certain HIV-associated illnesses, such as tuberculosis (TB), candidal infections, lymphomas, and Kaposi’s sarcoma (Figure 1). As CD4 counts fall, hosts are susceptible to more and more infections and cancers.
This group of patients often presents a challenge to the clinician because they may not fit “Occam’s razor”; they may have multiple infectious or oncologic complications at one time, instead of one unifying diagnosis. Additionally, many symptoms such as wasting, lymphadenopathy and diarrhea may be a manifestation of AIDS itself. Furthermore, patients can suffer systemic symptoms with immune reconstitution inflammatory syndrome (IRIS, discussed elsewhere). This can closely mimic disseminated infection.
Important points to remember are: 1) the level of immunocompromise dictates the differential diagnosis and what testing need to be ordered, and 2) regardless of degree of immunocompromise, individuals with HIV often suffer from common illnesses unrelated to their immunodeficiency.
II. Diagnostic Approach
A. What is the differential diagnosis for this problem?
In the pre-HAART era, infectious pulmonary complications were the predominant cause of morbidity and mortality in the HIV-infected population. Bacterial pneumonias, bronchitis and pneumocystis pneumonia were common causes of illness in this patient population. In the post-HAART era and with the advent of antimicrobial prophylaxis, the epidemiology of lung disease in HIV-infected individuals has changed. Bacterial pneumonia and pneumocystis pneumonia rates have decreased, and more non-infectious complications have emerged.
While HIV often conjures up thoughts of opportunistic infections, HIV-infected patients often fall prey to infections we see in immunocompetent individuals. Bacterial pneumonias are common in HIV-infected individuals, the most common isolated causative agent being Streptococcus pneumoniae, and occur more frequently as CD4 counts fall. The rates of bacterial pneumonia in patients with CD4 greater than 500 are similar to those of the general population, whereas patients with CD4 less than 200 are six times more likely to present with bacterial pneumonia. The highest risk individuals are injection drug users.
Pneumocystis pneumonia is one of the better known opportunistic infections in HIV-infected persons and typically occurs when the CD4 counts fall below 200. CMV pneumonia can contribute to pulmonary illness in patients with CD4 less than 100, though it is often thought to be a result of reactivation of virus, and more as a poor prognostic marker than as a sole cause of pulmonary symptoms.
TB is the most common pulmonary complication of HIV in the developing world. In the US, TB can occur in HIV-infected individuals at any CD4 count, but prevalence increases as immune function decreases. Untreated advanced HIV infection increases the chance of reactivation TB tenfold.
Endemic fungi such as Coccidioides immitis and Histoplasma can cause serious lung infections in patients infected with HIV. Aspergillusis a rare cause of tracheitis at CD4 counts below 50.
Interestingly, as more people gain access to HAART, pulmonary infectious complications of HIV are decreasing, giving way to a whole new class of non-infectious complications, including non AIDS-defining cancers (non-small cell lung cancer [NSCLC], Hodgkin’s lymphoma) and pulmonary hypertension. The rates of AIDS-defining cancers of the lung (Kaposi’s sarcoma, non-hodgkin’s lymphoma [NHL]) have fallen in the HAART era.
Gastrointestinal complications are common in HIV-infected individuals, and diarrhea is reported in up to 90% of patient with HIV. Infectious causes of diarrhea most often found on endoscopic biopsy are: Clostridium difficile, Salmonella, Shigella, Campylobacter, Giardia, Cryptosporidium, Isospora, Microspora, Strongyloides stercoralis, cytomegalovirus (CMV), and micobacterium avium complex (MAC).
Kaposi’s sarcoma and lymphoma can also affect the gastrointestinal (GI) tract, causing malabsorption and diarrhea. Lymphoma of the stomach is often diagnosed in late stage and presents with obstruction.
HIV enteropathy (direct HIV-infection of the gut cells) causes altered bowel motility, bacterial overgrowth and chronic diarrhea.
Odynophagia is another common symptom in advanced HIV infection and can be caused by esophageal candida, CMV, herpes simplex virus (HSV), Kaposi’s sarcoma, or aphthous ulcers.
Hepatobiliary disease in HIV-infected individuals can have a variety of etiologies. Rates of chronic hepatitis B virus (HBV) infection are higher and rates of progression to cirrhosis and decompensated liver failure are faster in HIV infection. Hepatitis C virus (HCV) prevalence is markedly elevated in HIV-infected individuals compared to age-matched controls. AIDS cholangiopathy, a syndrome of biliary obstruction, can occur with CD4 counts less than 100. Cryptosporidiosis, CMV and Giardia, MAC, disseminated TB, and histoplasmosis all have a propensity for the liver.
Kaposi’s sarcoma, NHL and cervical cancer can occur at any CD4 count in HIV-infected individuals and are termed AIDS-defining cancers. In the HAART era, it has become clear that HIV-infected individuals are also at increased risk for other malignancies. Most common appears to be lung cancer and HIV-infected individuals tend to present at a younger age than the general population.
Other cancers that occur with increased frequency in HIV-infected persons are: Hodgkin’s lymphoma (mostly Epstein-Barr virus [EBV]-associated), anal cancer (human papilloma virus [HPV]-associated) and liver cancer. While the pathophysiology is not completely understood, most of the cancers noted above are linked to a viral pathogen; it is postulated that the increased frequency of these cancers is due to immune suppression.
Central nervous system (CNS) lymphoma (Figure 2) is associated with a greater degree of immunosuppression than systemic NHL and occurs at CD4 less than 50. It is usually EBV-associated.
Patients with HIV presenting with acute to subacute meningoencephalitis may be presenting with primary HIV infection, CMV infection (CD4<50), cryptococcal meningitis (CD4<50), toxoplasma encephalitis (TE) (CD4<100), TB meningitis, or coccidiomycosis meningitis.
All the above infections can cause focal neurological symptoms such a seizure or hemiplegia. The rates of TE have decreased, as trimethoprim/sulfamethoxazole (TMP/SMX; Bactrim) Bactrim prophylaxis against pneumocystis is also active against this infection. HSV can cause either meningitis or encephalitis.
Progressive multifocal leukoencephalopathy (PML) is a central nervous system demyelinating neuropathy which presents with subacute changes in mental status, hemiparesis or ataxia when CD4 is less than 100. HIV is also associated with multiple peripheral neuropathies and myelopathies.
Primary CNS lymphoma is associated with severe immunosuppression and can present as lethargy, confusion and focal signs secondary to elevated intracranial pressure.
AIDS dementia (now called HIV-associated neurocognitive disorder) is characterized by chronic progressive motor, cognitive and behavioral abnormalities. In the pre-HAART era, the cognitive impairments seen were severe, but now mild forms are being recognized.
The most common cause of chronic kidney disease (CKD) in HIV-infected individuals is HIV-associated nephropathy (HIVAN), which is characterized by proteinuria, lack of hypertension and collapsing focal segmental glomerulosclerosis on renal biopsy. Other causes include immune complex disease, interstitial nephritis from medications or infections, thrombotic microangiopathies, and, as HIV-infected persons are living longer and healthier lives, diabetic and hypertensive nephropathy.
While hospitalized, HIV-infected individuals are at increased risk of developing acute kidney injury (AKI), which is associated with increased mortality. While in the pre-HAART era, most AKI was associated with opportunistic infection and septicemia, currently 38% of AKI is prerenal, and 48% is due to acute tubular necrosis (ATN), commonly from medications. Patients with lower CD4 counts are at greater risk for AKI.
Drug-related renal injury in these patients is often secondary to HAART, bacterial prophylaxis or agents used to treat opportunistic infections. Most commonly implicated are: trimethoprim-sulfamethoxazole, tenofovir, cidofovir, adefovir, quinolones, or foscarnet.
In recent years, a large body of data has been published that suggests an increased burden of cardiovascular disease in HIV-infected individuals.
The pathophysiology of this is likely multifactorial and involves: 1) the atherogenic nature of the virus, 2) the higher than usual prevalence of traditional risk factors in HIV-infected populations (smoking, intravenous drug user [IVDU]), 3) dyslipidemia and diabetes mellitus (DM) caused by protease inhibitors (PIs), and 4) direct atherogenic effect of the PIs and select nucleoside reverse-transcriptase inhibitors. Higher levels of pro-inflammatory cytokines during active viral replication also increase the risk of cardiovascular disease.
Systemic complications/disseminated disease
Though now more rarely seen due to the advent of HAART, disseminated diseases are still common in the developing world and may be the initial presentation of HIV. Mycobacteria avium complex (MAC) often presents with fever, weight loss, anemia, lymphadenopathy, diarrhea, and hepatitis. Histoplasmosis and coccidiomycosis present with systemic symptoms and commonly pulmonary disease. Bacillary angiomatosis (Bartonella infection) (Figure 3) presents with fever, malaise and vascular skin lesions.
CMV is rarely the sole cause of severe systemic disease, but it can infect any organ in the body, and causes CMV retinitis at CD4 counts less than 50.
B. Describe a diagnostic approach/method to the patient with this problem
The diagnostic approach will depend on a careful history and physical examination, in addition to understanding the patient’s HIV treatment history. A recent CD4 count (and preferably a recent trend) is the single most helpful element in formulating a differential diagnosis.
All HIV-infected individuals, regardless of CD4 count, are at increased risk of the following:
Cardiovascular and renal complications (may depend on current therapy)
TB (those with CD4 <200 are more likely to have extrapulmonary disease)
Bacterial enteric disease
Varicella zoster virus (VZV)
Human herpes virus 8 (HHV-8) (Kaposi’s sarcoma)
HPV (cervical and rectal cancers)
Histoplasmosis (pulmonary at any count, CD4 <150 for disseminated infection)
HIV-infected individuals with CD4 less than 200 are at risk for all of the above, and the following:
Toxoplasmosis (Figure 4)
Coccidioidomycosis (may have CD4 counts up to 250)
HIV-infected individuals with CD4 less than 100 are at risk for all of the above, and the following:
HIV-infected individuals with CD4 less than 50 are at risk for all of the above, and the following:
Aspergillosis (meningitis or pulmonary disease)
CMV (retinitis, esophagitis, colitis, CNS disease)
1. Historical information important in the diagnosis of this problem.
Important questions to ask include the following:
Careful history and timing of chief complaint
-There may be more than one diagnosis
History of HAART and adherence
– Presentation may be related to drug side effects
Any bacterial prophylaxis and adherence
– If on Bactrim prophylaxis, less likely to have bacterial pneumonia, pneumocystis or toxoplasmosis
– If taking azithromycin, less likely to acquire MAC
CD4 count and history
– Previous AIDS-defining illness or CD4 count less than 200 predisposes to more serious infection even if counts are currently above 200
– Mississippi River valley for histoplasmosis
– Southwest US for coccidioidomycosis
– Foreign TB endemic area
Careful sexual history for epidemiology
-Kaposi’s sarcoma is much more common in men that have sex with men (MSM)
Secondary syphilis can cause high fevers, rash, and mental status changes
Giardia is more common in MSM
Anal intercourse may be linked to anal cancer
Careful social history
– IVDU increases risk for bacterial pneumonia, TB and viral hepatitis
Smoking increases the risk for lung cancer and heart disease
2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
This chapter focuses on a variety of clinical problems that affect virtually all organ systems; please see disease-specific chapters for physical exam pearls.
In the scope of focusing on a HIV-infected individual presenting to a hospital setting, it is of utmost importance to perform a thorough physical examination, including skin, oropharynx, and abdominal exam regardless of the chief complaint. Skin findings such as Kaposi’s or bacillary lesions can suggest level of immunocompromise and point at the causative process. Organomegaly and lymphadenopathy can suggest the presence of a systemic process.
3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
The initial evaluation of the HIV-infected patient with pulmonary symptoms involves a chest radiograph, which helps differentiate between focal and diffuse pneumonias. Sputum sample can guide treatment, but often treatment is based on epidemiology. Blood cultures may be helpful in bacterial pneumonia.
If there is suspicion of TB based on presentation and risk, the patient should be isolated in a negative-pressure setting and sputum samples for acid-fast bacilli (AFB) smear should be obtained.
If there is severe hypoxia and pneumocystis pneumonia is suspected, an arterial blood gas will help guide the use of corticosteroids based on degree of arterial hypoxemia. At times, a computed tomography (CT) scan is required to better characterize the pulmonary process and bronchoscopy may be required if an infectious agent is suspected but has not been isolated or if malignancy is suspected.
Histoplasma antigen in serum or urine can detect disseminated histoplasmosis but is insensitive for pulmonary infection.
A transthoracic echocardiogram is useful when HIV-associated pulmonary hypertension is suspected.
The evaluation of patients with HIV and diarrhea pivots around stool culture data, including careful examination for ova (with acid fast [AF] technique) and parasites. Up to 50% stool samples obtained fail to identify a causative organism. The most appropriate endoscopic approach to HIV-infected patients with unrelenting diarrhea is unclear, but colonoscopy with ileal intubation appears to have the highest yield for new diagnoses, especially for microsporidium and CMV. If the ileum cannot be intubated, upper endoscopy may be needed for small bowel biopsy.
Yields are usually highest with endoscopy for patients with CD4 less than 100 and with systemic symptoms.
The approach to the HIV-infected patient who presents with hepatobiliary complaints is similar to the approach in an immunocompetent patient and includes hepatic panel, imaging and endoscopic retrograde cholangiopancreatography (ERCP) if necessary, and broad-spectrum antibiotic therapy if there is evidence of cholangitis.
The approach to the patient with HIV infection and neurologic symptoms begins with a cranial CT. Contrast-enhanced cranial CT and/or magnetic resonance imaging (MRI) will identify mass lesions, and enhancement can give a clue to the diagnosis.
Lumbar puncture (LP) is contraindicated in lesions with mass effect. For mass lesions, typically multiple lesions that are ring-enhancing are consistent with TE.
CNS lymphoma lesions are often supratentorial and multicentric, enhance uniformly and have surrounding edema. However, the two lesions can present very similarly and can be hard to distinguish radiographically.
Stereotactic brain biopsy is the gold standard in diagnosing mass lesions in the CNS in HIV-infected individuals. This is an invasive procedure, and though mortality rates are generally low, they have been reported as high as 9%. Several strategies are used in order to attempt to avoid biopsy.
If the radiographic appearance is consistent with TE and serum antigen for toxoplasma is positive, patients often get empirically treated for TE and response to therapy guides the diagnosis. Also there are some promising results with using single positron emission CT (SPECT) to differentiate between malignancy and infection, but this test is expensive and not uniformly available.
Non-mass lesions of the CNS are better characterized with MRI which can show typical appearance PML, cryptococcal pseudocysts if present, HIV, and CMV encephalitis.
LP can be an aid in diagnosis in non-mass-occupying lesions. Cerebrospinal fluid (CSF) JCV polymerase chain reaction (PCR) has 95% specificity for PML. CSF CMV PCR specificity for CMV encephalitis exceeds 90%. Cryptococcal antigen in the CSF is highly specific for cryptococcal meningitis and usually found in high titer in the CSF. If there is evidence of increased opening pressure, these patients will need serial LPs in addition to antifungal therapy.
Tuberculous meningitis at times has focal imaging presentations but should be suspected in subacute to chronic meningitis in a patient with high risk or previous exposure to TB; it is not ruled out by negative CSF AF smear or culture.
The diagnosis of AIDS cognitive disorder is based on a history of cognitive decline and neuropsychiatric testing.
Most cases of AKI in patients with HIV who are hospitalized are either medication-related or secondary to hypovolemia, and can be secondary to an infection causing a prerenal state. A careful review of medications and recent changes in doses or additions is warranted.
A renal biopsy is usually not warranted, unless this is the primary presentation or suspected to be HIVAN or immune complex disease, based on history, proteinuria or ongoing chronic infection.
HIV-infected individuals should be evaluated in exactly the same way as patients without immunodeficiency in the face of cardiac symptoms. The important thing to keep in mind is that this is likely a high-risk population for development of coronary artery disease.
Biopsy is typically diagnostic, thought Kaposi’s sarcoma lesions are very characteristic by clinical exam.
When disseminated disease is suspected, blood cultures are helpful for implicating MAC infection. Biopsy is the most sensitive means of arriving at the causative organism in MAC, coccidioidomycosis and bacillary angiomatosis. Histoplasma urinary and serum antigen are more than 90% sensitive for disseminated infection. Cryptococcal antigen in serum is suggestive of disseminated Cryptococcus and requires LP to rule out CSF involvement.
It is important to keep in mind that a patient presenting with systemic symptoms in this population can be exhibiting IRIS, especially in the setting of recent initiation of HAART. The pathophysiology of IRIS is not completely understood, but may be the manifestation of an immune system that is “waking up” and responding to large amounts of antigen it did not recognize before. These patients usually exhibit systemic symptoms within 3 months of starting HAART (but can have symptoms years later), have more severe responses the lower their CD4 nadir and usually react against infections that they have had in the past (CMV, HCV/HBV, MAC, Cryptococcus, TB).
C. Criteria for Diagnosing Each Diagnosis in the Method Above.
Please see disease-specific chapters for exact diagnostic criteria.
D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
This is a population of patients, especially the ones with severe immunocompromise, in which it is worthwhile to cast a wide net for diagnostic purposes. HIV-infected patients often have extended hospital stays, and undergo multiple costly tests and procedures. This is hard to avoid because of the high morbidity and mortality associated with complications of this disease.
The utility of obtaining a CD4 count in the setting of acute illness is questionable. There is a body of literature showing that patients with acute illness in the intensive care unit (ICU) have falsely depressed CD4 counts even if they do not have HIV infection. This likely applies to HIV patients with acute illness; the CD4 count obtained will be falsely low leading to unnecessary investigations. Thus, if a patient has a recent CD4 count from an outpatient clinic, it is appropriate to assume those are accurate and forego obtaining a new confounding lab in the hospital.
That said, patients with a new diagnosis and no previous CD4 count should have one obtained on presentation.
Also, viral loads obtained in the hospital are often seen, but there are usually no therapeutic decisions that depend on them.
III. Management while the Diagnostic Process is Proceeding
A. Management of complications of human immunodeficiency virus.
The severity of presenting illness will dictate the amount of resuscitative effort. After stabilization, a focused investigation should be expedited based on presenting symptoms and likelihood of particular diseases based on level of immunocompromise. If the patient does not have a previous CD4 count, one should be obtained.
In general, presentations of acute and subacute meningitis or meningoencephalitis can often be fatal if not treated rapidly, thus a timely investigation should be performed to isolate the causative organism. As stated previously, CNS lymphoma and TE may often be hard to distinguish from each other radiographically. If such a case arose clinically, it would be reasonable to treat for TE while undergoing further evaluation, especially if toxoplasma serum antigen is positive.
In general, it is not appropriate to initiate an antibiotic regimen for diarrhea for which a causative agent has not been identified.
In the setting of severe hypoxia, if pneumocystis is suspected, obtain an arterial blood gas (ABG) as this will determine whether or not to initiate steroids prior to antibiotic therapy. Empiric treatment for pneumocystis is not generally recommended, unless the patient is critically ill. Mortality from pneumocystis has decreased 21% to less than 10% in the HAART era, but there is data to suggest this may not be true in areas with a more underserved population who receive less HAART therapy.
Do not forget to consider TB in patients who have risk factors. HIV infection greatly increases the risk of reactivation of TB. Isolate these patients in negative pressure if pulmonary TB is suspected.
For management of specific complications once diagnosed, please see disease-specific chapters.
It is ideal in these cases to have the help of a specialist who has experience in HIV, not only to aid with the diagnosis, but also to make decisions about whether to stop or continue HAART as it relates to the acute illness, and when to start HAART if the patient is not currently on antiretrovirals. The guidelines for these decisions are changing and the decision process is complex and disease-dependent.
B. Common Pitfalls and Side-Effects of Management of this Clinical Problem
Generally, both HAART and specific treatments for the conditions above have significant toxicities. Please see disease-specific chapters for a discussion on those and specific treatment regimens.
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- Complications of human immunodeficiency virus
- I. Problem/Condition.
- II. Diagnostic Approach
- A. What is the differential diagnosis for this problem?
- B. Describe a diagnostic approach/method to the patient with this problem
- 1. Historical information important in the diagnosis of this problem.
- 2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
- 3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
- C. Criteria for Diagnosing Each Diagnosis in the Method Above.
- D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
- III. Management while the Diagnostic Process is Proceeding
- A. Management of complications of human immunodeficiency virus.
- B. Common Pitfalls and Side-Effects of Management of this Clinical Problem