Critical Care Medicine

Infection in the (non-transplant) patient on immunosuppressive medications

Pulmonary infections with respiratory compromise

conventional pyogenic bacteria‡, mycoplasma, chlamydia spp., legionella, Mycobacterium tuberculosis (M-TB), Pneumocystis jiroveci, Strongyloides stercoralis, endemic mycoses¶, aspergillus, cryptococcus, non-tuberculous mycobacteria (NTM*), nocardiosis, actinomycosis, cytomegalovirus (CMV), herpes simplex virus ( HSV), varicella zoster virus (VZV), pneumonitis and other respiratory viral pneumonias.†

‡ S. pneumonia, H. influenza, K. pneumoniae, S. aureus, M. catarrhalis.

¶ Histoplasmosis, coccidioidomycosis, blastomycosis, penicilliosis, paracoccidioidomycosis.

*Mycobacterium avium intracellulare (MAC), M. Kansasii and other NTM ( M. chelonae, M. abscessuss, M. fortuitum: rapidly growing mycobacteria (RGM), M. xenopi, M. malmoense, M. szulgai).

†: Influenza, parainfluenza, adenovirus, respiratory syncitial virus (RSV), metapneumovirus.

CNS infections

Pyogenic pathogens (S. pneumonia, N. meningitidis, H. influenza, Gr.B streptococcus, Gram – rods), unusual pathogens: Listeria, nocardia, M-TB, cryptococcus, toxoplasma, aspergillus, endemic mycoses, progressive multifocal leukoencephalopathy secondary to JC virus, Herpes simplex virus (HSV-1/2), CMV, and other viruses, spirochetal and rickettsial diseases (see Table 1).

Infections with multi-organ involvement‡

Disseminated histoplasmosis, coccidioidomycosis, cryptococcosis, tuberculosis, aspergillosis, Varicella zoster virus related infections (VZV): Primary infection (varicella), disseminated herpes zoster (DHZ), NTM infections (MAC), disseminated strongyloidiasis.

Infections in the non-transplant patient on immunosuppressive medications

Synonyms

Legionnaires' disease (legionella), (PCP) Pneumocystis jiroveci, ¶, coccidioidomycosis (valley fever, desert rheumatism), cryptococcosis, listeriosis, nocardiosis, Toxoplasmosis, progressive multifocal leukoencephalopathy (PML), non-tuberculous mycobacteria (NTM*), CMV, HSV, VZV pneumonitis and other respiratory viral pneumonias.†

Related conditions

Pulmonary infections with respiratory compromise. Central nervous system (CNS) infections. Infections with multi-organ involvement. Fever/sepsis localizing to the skin, opportunistic infections and biologics, meningitis, meningoencephalitis, pneumonia, skin nodules, pulmonary infiltrates, brain lesions.

1. Description of the problem

Although this chapter emphasizes opportunistic infections, any agent that can infect a normal host can affect the non-transplant patient on immunosuppressive medications.

Pulmonary infections with respiratory compromise

There is significant overlap among different pathogens. Hypoxemia and tachypnea are hallmark symptoms of respiratory compromise. Conventional pyogenic organisms remain the most common offenders among immunocompromised hosts. They are usually confined to the lung but are locally invasive (parapneumonic effusion, empyema, lung abscess). They are frequently associated with purulent sputum, pleuritic chest pain, lobar consolidation and sepsis.

P. jiroveci: marked hypoxemia worsened with minimal exertion (drop of O2 saturation by >5%), dyspnea and cough with few findings on physical exam. More rapid onset compared with AIDS associated pneumocystis. It often flares with steroid tapering.

Legionella: Flu-like illness with high fever, bradycardia, abdominal pain, cough often accompanied with diarrhea which could be the initial symptom, followed shortly with hypotension, dyspnea and confusion.

Primary pulmonary histoplasmosis and coccidioidomycosis are usually self-limited in immunocompetent hosts; however, they present with flu-like symptoms associated with hypoxemia, wheezing, weight loss, and sometimes rheumatologic manifestations (erythema multiforme, arthritis, erythema nodosum), in an immunocompromised host. Enlarged hilar and mediastinal lymph nodes are present in 10% of patients.

Invasive pulmonary aspergillosis is a febrile pneumonia that is refractory to broad spectrum antibiotics. Due to its angioinvasive nature, hemoptysis, pleuritic chest pain and hypoxemia are common findings. Primary pulmonary aspergillosis occurs frequently among patients with chronic parenchymal disease.

M-TBand M. kansasii are almost identical. Fever may be less prominent with M. kansasii. MAC coexist with underlying chronic lung disease (COPD, bronchiectasis) and its clinical presentation resembles M-TB. Extensive lung involvement (three or more lobes in more than 50% of cases) with significant respiratory compromise, and likely extrapulmonary disease are common findings by the time patients present to ICU.

Listeria, toxoplasma, M-TB, cryptococcus and other fungal infections: fever, headache, altered sensorium, focal neurologic deficit (cranial nerve palsies, ataxia, tremor and hemiparesis) and focal or generalized seizures.

Listeria: brain stem encephalitis (rhomboencephalitis) preceded or accompanied with gastrointestinal symptoms and bacteremia.

M-TB and cryptococcosis: subacute presentation over days to weeks. Molluscum-like lesions on the skin are suggestive of cryptococcal infection. The initial pulmonary focus (nodular/ cavitary pneumonia) may or may not be present.

Progressive multifocal leukoencephalopathy (PML): Hemiparesis, ataxia, visual symptoms such as hemianopia, diplopia, seizure and altered mental status over days to weeks.

HSV-1, and rarely HSV-2, cause psychiatric symptoms as a result of frontal lobe involvement but may also cause temporal lobe signs including olfactory and auditory hallucinations, hypomania, amnesia and seizures.

VZV: acute cerebellar ataxia and diffuse encephalitis with focal deficits can be seen. A stroke of unknown origin in immunosuppressed patient should evoke VZV due to the vasculopathic effect of the virus.

Infections with multi-organ involvement‡

‡3 or more organs:

- Lung

- CNS (brain, leptomeninges, spinal cord)

- Mucocutaneous

- Musculoskeletal (muscle, joints, bone)

- Lymph nodes distant from primary focus

- Gastrointestinal

- Bone marrow

- Other organs (eyes, heart, etc…)

Many pathogens with predilection to the lower respiratory tract and CNS (M-TB, NTM, endemic mycoses, nocardia, aspergillus, strongyloidisasis and others), will disseminate to other organs. These agents are associated with a clinical spectrum that varies from a single complaint, as simple as cough, to respiratory failure and multi-organ involvement. The presenting syndrome depends on when these pathogens are intercepted during their invasion of the host. In critically ill patients, although respiratory compromise is the dominant syndrome, many patients will have extra-pulmonary findings that could alter the diagnostic and therapeutic plan.

Disseminated MAC: febrile illness, weight loss, diarrhea, abdominal pain; associated with hepatosplenomegaly, pancytopenia and elevated liver enzymes.

Disseminated histoplasmosis (DH): a prolonged febrile illness, weight loss, worsening cough, hepatosplenomegaly, lymphadenopathy, hyperbilirubinemia, and pancytopenia, followed with an acute decline in respiratory function and sepsis. 5-20% of patients with DH have CNS involvement. Acute adrenal insufficiency develops in 5-10% of cases. Macular involvement may cause blindness. (Figure 1)

Figure 1.

Choroiditis (posterior uveitis) illl-defined pale, atrophic patchy areas

Coccidioidomycosis, like histoplasmosis, can spread beyond the lung parenchyma to involve many organs with predilection to the skin, bone, joints and CNS. The triad of arthralgias, fever and erythema nodosum labeled as “desert rheumatism” may be the presenting triad in 25% of cases. The presence of systemic complaints, prominent hilar/mediastinal adenopathies and diffuse infiltrates are indicators of severe disease with likely dissemination. Disseminated cryptococcosis presents as a febrile illness with umbilicated nodular skin lesions and meningitis. (Figure 2) Macular and peritoneal involvement has been reported.

Figure 2.

Molluscum-like lesion associated with disseminated cryptococcal infection

Disseminated strongyloidiasis: Waxing and waning of asthma-like attacks with eosinophilia complicated with acute pneumonitis, overwhelming sepsis, ARDS and polymicrobial Gram negative bacteremia/candidemia shortly after initiation of immunosuppressive therapy. Diffuse abdominal pain and bloating plus meningeal symptoms may be present. Steroids are the lead predisposing immunosuppressive agents.

Disseminated mycobacterial infections (M-TB, NTM), endemic mycosis, strongyloidiasis, involve: CNS, skin, liver, spleen, lymph nodes, bone, joints, muscle, bone marrow, eyes and heart valve. These complications can sometimes be hard to distinguish from the expression of the underlying auto immune disease or toxicities of therapy (Table IV).

Cutaneous (nodular lesions that may ulcerate, nodular lymphangitis), lymphadenitis (with or without a draining sinus), and deep seated structures (bursitis, tenosynovitis, osteomyelitis and septic arthritis) involvement, are very common in NTM infections.

VZV divided into (a) primary infection (varicella): crops of vesicular hemorrhagic skin lesions with pneumonia similar to P. jiroveci, encephalitis, and disseminated intravascular coagulopathy (DIC); and (b) reactivation (herpes zoster), which can disseminate (DH) following immunosuppressive therapy: acute neuritis affecting thoracic or lumbar dermatome followed by a papular rash which quickly evolves into a vesicular/pustular rash associated with headache, fever and malaise in 20% of cases.

Involvement of trigeminal dermatome can be sight-threatening, especially when hyperemic conjunctivitis is associated with vesicular lesions involving the tip and bridge of the nose. Blurred vision and pain in the affected eye may be a sign of impending acute retinal necrosis.

Aseptic meningitis occurs in 40-50% of cases, motor deficit due to a transverse myelitis and encephalitis are rare complications. Systemic involvement without a rash is a rare event.

CMV:Reactivation of CMV can occur at anytime following intense cell-mediated immunosuppression. Although more common in post transplant, it has been seen in patients on antilymphocytes therapy especially following an acute illness. CMV is associated with pneumonitis (interstitial, reticulonodular infiltrates), colitis, retinitis, encephalitis and rarely myocarditis.

Key management point:

Aggressive attempt for a diagnosis (historical clues/physical exam/labs/preliminary microbiologic work-up)

A. Define the epidemiologic circumstances surrounding the onset of the disease (see epidemiology section):

- Detailed social, occupational exposures, thorough recent/previous travel and residential history.

- Country of high incidence:

  • M-TB: (Eastern Europe, Sub-Saharan Africa, central and south America, Southeast Asia). History of incarceration greater than 6 months and /or homelessness.

  • Histoplasmosis: (most common worldwide, Ohio and Mississippi River Valleys).

  • Cocciodiomycosis: (South Arizona, Utah, California, West Texas, South New Mexico and northern Mexico)

  • Blastomycosis: (midwestern, south-eastern, south central U.S.).

  • Strongyloides: common among immigrants, travelers and military personnel from tropical and subtropical regions (South eastern states, south east Asia); persists for many years after exposure.

  • Listeria: food-born illness.

  • Legionella and aspergillus: Construction sites.

  • Legionella: whirlpool spas, decorative fountains. Epidemic outbreaks on cruise ship and close knit communities.

  • VZV: contact with children, recent outbreak, lack of vaccination.

  • Influenza, respiratory syncitial virus (RSV), metapneumovirus outbreaks, cause disease between November through April. Adenovirus and parainfluenza outbreaks, are perennial.

B. Tempo of the disease:

  • Acute: within 3 days (S. pneumonia, N. meningitidis, H. influenza, B streptococcal, Klebsiella, S. Aureus, legionella, HSV, VZV, Influenza, RSV, NTM, disseminated strongyloidiasis, acute pulmonary histoplasmosis).

  • Subacute to chronic: 3-5 days or more (Listeria, Nocardia, M-TB, Cryptococcus, Toxoplasma, Aspergillosis, Histoplasmosis, Coccidioidomycosis, NTM, Nocardia, P. jiroveci, Cryptococcus, Actinomycosis, PML).

C. Net state of immunosuppression:

  • Define the underlying disease: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and other associated co- morbidities: chronic renal insufficiency, diabetes, smoking, COPD, all of which affect the host defense barriers.

  • Define which arm of the immune system is affected by the immunosuppressive therapy (Table II)

D. Comprehensive physical exam (diagnostic clues):

  • Skin nodules: disseminated NTM, fungal infection, bartonella.

  • Erythema nodosum: M-TB, NTM, histoplasmosis, coccidioidomycosis.

  • Molluscum-like lesions: Cryptococcus.

  • Papular eruption with crusting/tongue ulcer: Chronic DH.

  • Nasolabial eruption/ulceration: coccidioidomycosis.

  • Enlarged cervical lymphadenopathy(ies) with a draining sinus: NTM.

  • Retinal hemorrhage: CMV retinitis most common, cryptococcis, P. jirovecii.

  • Jaundice + hepatosplenomegaly: infiltrative liver disease (NTM, DH, M-TB).

  • Wheezing + periumbilical purpura: disseminated strongyloidiasis.

  • Nodular lymphangitis: M. marinum, sporotrichosis, nocardiosis.

  • Cranial nerve palsy: M-TB, listeria, coccidioidomycosis, DH.

2. Emergency Management

  • Intensive support of the host homeostasis: stabilize respiration and monitor pulse oximetry continuously.

  • Assess and restore perfusion.

  • Electrolytes, CBCD, liver and kidney functions, LDH, ANCA, Anti GBM antibodies, urinalysis + sediment, minimum 2 sets of blood cultures and radiographic clues (see Table III).

  • Prompt empirical therapy guided by collected data.

  • Control the source of sepsis with drainage if needed (by interventional radiology, or surgical).

Management points not to be missed

Pulmonary infections with respiratory compromise:

  1. Airborne precautions if miliary or pulmonary M-TB, measles, chickenpox or disseminated zoster are suspected.

  2. Obtain “good” sputum, preferably via bronchoscopy, for gram stain, fungal and AFB smears and corresponding cultures, plus viral respiratory direct fluorescent antibody (DFA) and silver stain for PCP, and wet mount for filariform larvae if disseminated strongyloidiasis is suspected.

  3. Initiate Empiric antibiotic¶ therapy targeting likely pathogens within 6 hours from time of admission, and hold or decrease immunosuppressive therapy.

  4. Perform thoracentesis and pericardiocentesis in patients with significant pleural and or pericardial effusions, with a respiratory and hemodynamic compromise respectively.

  5. Further imaging studies: CT scan of lung with IV contrast if GFR permits plus imaging of any clinically meaningful site.

  6. Plan for aggressive procedures as needed: broncho-alveolar lavage (BAL), trans-bronchial biopsy (TBBX), video-assisted thoracoscopy (VATS), open biopsy if preliminary tests are unrevealing

¶ Common bacterial infections remain the leading cause of infection: Ceftriaxone 2 gms daily or cefotaxime 2 gms Q8hr + Azithromycin 500 mg IV qd or Levofloxacin 750 mg qd or Moxifloxacin 400 mg qd. If Pseudomonas aeuroginosa is suspected substitute 3rd generation cephalosporin with cefipime 2 gms IV q8hr or Meropenem 1 gm IV q8 or Piperacillin-tazobactam 4.5 gms q6hr plus a quinolone (levofloxacin 750 mg qd, or Moxifloxacin 400 mg qd). For methicilline resistant S. aureus (MRSA) vancomycin 15-20 mg/kg q12 hrs in patient with normal renal function. Keep vancomycin trough between 15 to 20 mg/L, or Linezolid 600 mg q12 hrs. Daptomycin has poor lung penetration and should not be used.

CNS infections:

Non focal neurologic evaluation plus meningismus without an impaired sensorium:

  1. Perform lumbar puncture and Initiate empirical antibiotic therapy and dexamethasone* within 30 minutes from LP, a minimum 2 sets of blood cultures, electrolytes, CBCD, liver and kidney functions, serum cryptococcal Ag.

  2. Focal neurologic deficit, obtunded mental status, seizures, papilledema: Obtain laboratories, initiate empirical antibiotic therapy and dexamethasone,* obtain imaging studies before LP.

  3. Imaging studies of CNS: CT-scan with and without contrast, MRI with Gadolinium.

  4. Empirical antimicrobial therapy should be targeted against the most likely pathogens: Ceftriaxone 2gr IV q12 or cefotaxime 2gr IV q6hr + Vancomycin 30 to 60 mg/dL IV per day + ampicillin 2 gms IV q4hrs + Acyclovir 10 mg/kg IV q8hr. Some experts recommend adding rifampin if S. pneumoniae is suspected and and dexamethasone has been initiated.

  5. Reduce intracranial pressure by elevating the head of the bed to 30 degrees, maintain PaCO2 between 27 and 30mmHg and use hyperosmolar agents.

  6. Discontinue immunosuppressive therapy. Patient on chronic steroid therapy should receive physiologic replacement therapy.

*: Dexamethasone (DXM) 0.15 mg/kg if high suspicion of pyogenic bacterial meningitis, and when substantial perilesional edema with mass effect are present in association with depressed mental status.

Infections with multi-organ involvement:

  1. Plan for skin or lymph node biopsy (preferably excisional) when possible. If these tests are unrevealing in patients with pulmonary infiltrates proceed with a BAL, TBBX, VATS or open biopsy as needed.

  2. Musculoskeletal imaging of any clinical meaningful site should be used to determine extent of infection, guide needle aspiration and monitor treatment.

  3. Hold or decrease immunosuppressive therapy.

  4. Empirical therapy should be initiated ideally after tissue is obtained targeting likely pathogens. It can be guided by rapid assays (stain, DFA, PCR, Ag detection) applied to specimens whenever available. If an invasive skin infection is the dominant component of the systemic illness, start Ampicillin-sulbactam 3 gms IV q6hrs or Piperacillin-tazobactam 4.5 grs IV q8hr if recent hospitalization/ nursing home patients, ± clindamycin 900 mg IV q8hr (if necrotizing faciitis/toxic shock syndrome suspected), plus vancomycin 15-20 mg/kg q12hr (keep MRSA coverage until excluded by cultures). Aggressive surgery is indicated when necrotizing infections are suspected (necrotizing fasciitis, gaz gangrene, synergistic necrotizing cellulitis, pyomyositis).

  5. (a) Place patient in a negative pressure room if VZV/ DHZ suspected; (b) define areas involved; (c) zoster ophtalmicus is an ophthalmic emergency; (d) initiate intravenous acyclovir ASAP; (e) if myelitis is suspected obtain MRI of thoraco-lumbar spine followed by an LP; and (f) aggressive pain control.

3. Diagnosis

Pulmonary infections with respiratory compromise

A. Radiographic pattern associated with respiratory pathogens (see Table III)

  • No radiographic pattern on CXR is pathognomonic for any illness.

  • High resolution CT scan is a more sensitive and specific study. Tree-in-bud ( Figure 3) associated with bronchogenic spread of granulomatous infections (M-TB, NTM, endemic fungi), aspiration, infectious bronchiolitis, and connective tissue disorders.

  • Thin wall cavity/cavities with nodular lesions and hilar/mediastinal adenopathies: histoplasmosis, coccidioidomycosis, nocardiosis.

  • Dense, well circumscribed lesion(s), with or without a halo sign, air-crescent sign or cavity: aspergillosis. Minor radiographic abnormalities require further investigation (CT scan).

  • Diffuse homogenous ground-glass opacities with sharp demarcation by interlobular septa are associated with P. jiroveci and early interstitial lung disease (Figure 4). While pneumothorax is suggestive of PCP, pleural effusions and and intrathoracic nodes are rare and should suggest a different pathology.

  • Calcified nodules, lymph nodes or splenic lesions: past infection with endemic fungi/ M-TB.\

  • False negative CXR are occasionally encountered in profoundly neutropenic patients, elderly, and with early P. jiroveci.

Figure 3.

Tree-in-bud infiltrate in NTM associated pneumonia

Figure 4.

Ground-glass infiltrate associated with P. jirovecii

B. Biologic markers

Procalcitonin can help distinguish between bacterial and non-bacterial pneumonia. A procacitonin level less than 0.1mcg/L is suggestive of viral pneumonias. A steadily increasing level correlates with a worse prognosis. High LDH and (1-3) beta-D-glucan, suggestive but not specific of P. jiroveci, appear to reflect the degree of lung injury and should decline with successful therapy.

Hyponatremia, hypophosphatemia, elevated CK and CRP greater than 30mg/L are seen with legionella and severe pneumococcal pneumonia. Hypereosinophelia associated with strongyloidiasis prior to dissemination. Normal to low eosinophil count post-dissemination.

Elevated alkaline phosphatase & gamma-GT: M-TB, NTM, histoplasmosis, pancytopenia and transaminitis are common with disseminated VZV, CMV, NTM, miliary M-TB and endemic mycosis.

C. Microbiologic clues with rapid turnaround time

1- Sputum staining:

Sputum ideally obtained via bronchoscopy, if the lesions are centrally located or diffuse. TBBX should often accompany BAL if there are no contraindications to enhance diagnostic yield. Notify lab if you are looking for coccidioidomycosis spherules, due to the high risk of transmission.

  • Gram stain: gram + cocci in clusters: staphylococcus Aureus; Gram + diplococci: streptococcus pneumoniae; Gram - cocobacilli: hemophilus influenzae; Gram - rods: Klebsiella pneumoniae, pseudomonas aeuroginosa, stenotrophomonas maltophilia.

  • Fungal stain: histoplasmosis, coccidioidomycosis, blastomycosis.

  • Modified AFB stain: nocardia.

  • AFB stain: M-TB, NTM.

  • India Ink, mucicarmin stain: encapsulated cryptococcus.

  • Silver stain: P. jiroveci.

  • Filariform larvae: Strongyloides.

2- Urinary antigen:

Legionella antigen very sensitive but detects only L. Pneumophila serogroup 1, which accounts for 70-80% cases.

S. pneumoniae antigen is more sensitive than sputum staining and cultures but not in non-bacteremic patients.

Histoplasma antigen positive in 90% of acute DH, 40% of cavitary disease.

3- Rapid Direct Immunoflurorescence assay:

Same day. Excellent for all herpes viruses. Very specific and reproducible.

4- Polymerase chain reaction:

More sensitive for the detection of atypical pathogens and viruses.

Result available in 6-30 hours.

No added value in terms of pathogen antibiotic sensitivity testing.

5- Serum antigen detection:

Cryptococcal antigen, galactomannan, 1-3beta-glucan assay (aspergillosis). False positive results can be seen in patients receiving piperacillin-tazobactam and amoxicillin-clavulanate. 6- Rapid viral antigen panel:

RSV, Parainfluenzae 1 ,2 & 3, Influenzae A/B, adenovirus.

Diagnostic tools with slower turnaround time:

  1. Histopathology and cultures.

  2. CT-guided biopsy (peripheral lesion) or VATS, or open biopsy can be performed in patients where BAL/TBBX is none-diagnostic or not feasible..

  3. US guided thoracentesis/pleural biopsy: histopathology and cultures.

  4. Blood cultures with lysis-centrifugation technique (endemic mycoses), AFB blood isolators, blood CMV antigenemia.

  5. Blood serologies are the least useful to diagnose active infection in immunocompromised hosts.

  6. Two concentrated stool specimens and incubation on agar plate looking for crawling larvae (2 days). If stool exam is negative a duodenojejunal aspiration may be helpful (strongyloidiasis).

CNS infections

Lumbar puncture

Opening pressure: normal up to 200 mm H2O. 300mmH2O or more is suggestive of bacterial or cryptococcal. meningitis.

CSF analysis: normal CSF WBC less than 5/microL, less than 50mg/dl protein, Glucose CSF/serum greater than 0.6, lactate less than 3.5 meq/L. True WBC in CSF post traumatic tap is derived as follows:

True WBC in CSF (corrected) = Actual WBC in CSF - WBC in blood X RBC in CSF / RBC in blood.

Common pyogenic bacterial infections are highly likely if WBC is greater than 100 microL and more than 80% neutrophils, or CSF glucose/serum is less than 0.4, or CSF glucose is less than 34 mg/dl, or protein concentration is greater than 220 mg/dl or lactic acid is greater than 6 mmol/L.

Gram stain sensitivity 60-90% and specificity is close to 100%; G+diplococcic: S. pneumonia; G-diplococci : N.meningitidis; small pleomorphic G-coccobacilli: H.influenzae.

PCR: simultaneous single-tube PCR for the detection of N. Meningitidis, S. pneumonia and H. influenzae type-b, permits a rapid diagnosis of the three pathogens that cause most bacterial meningitis with high accuracy, although false positives have been reported. It is not widely available.

Listeria: pleocytosis, predominantly neutrophilic or lymphocytic, and sometimes 50% of each. “Tumbling motility” in wet mounts of CSF. One third of patients have G+rods and cocobacilli. CSF culture is highly sensitive with meningitis. Blood cultures are more sensitive than CSF cultures with a focal brain abscess or rhomboencephalitis (61% vs 41% respectively). Listeria should be contemplated when “diphteroids” are reported to be growing from blood.

M-TB and NTM: mononuclear pleocytosis (100-500 cells/microL), very low glucose (<45mg/dl) and high protein (100-500 mg/dl). Three LP are recommended at daily intervals, with 10-15 ml of fluid obtained, to enhance the yield of CSF AFB smears and cultures. PCR for M-TB can be very helpful when positive, but if negative should not deny empirical therapy pending cultures.

Cryptococcal: elevated opening pressure (>70%), pleocytosis can vary from very few cells to 200 cells/mm3, predominantly mononuclear. Low glucose and elevated proteins are common. India ink is 50-70% sensitive. Cryptococcal Ag (hours) and cultures (3-5 days) are almost always positive. A normal CSF biochemistry does not rule out meningitis.

Toxoplasma: CSF is non specific, showing mild pleocytosis, elevated proteins, normal glucose and rarely hypoglycorrachia. If brain biopsy is not feasible and the diagnosis of toxoplasma remains questionable, a PCR on CNS fluid for T. gondii DNA can be helpful.

Coccidioidomycosis and histoplasmosis: CSF reveals a lymphocytic pleocytosis with elevated proteins and hypoglycorrachia. Coccidioidomycosis is the most common cause of eosinophilic meningitis in the U.S. PCR and antigen detection in CSF are very useful when antibodies production is compromised. Staining and culture low yield (8-10 mL) of CSF needed.

PML: Non specific CSF profile. PCR of JC virus DNA is the gold standard test, with a sensitivity of 74-93% and a specificity of 92-100%.

HSV-1/2: Lymphocytic pleocytosis with an elevated number of RBC and high protein. PCR is the gold standard test, highly sensitive and specific (98% and 100% respectively). Viral culture is rarely positive.

VZV/DH: mononuclear pleocytosis (<100 cells/microL) with an elevated number of RBC and high protein. Antigen detection via DFA or real-time PCR more sensitive than cultures.

Imaging studies

Listeria: MRI with IV gadolinium is more sensitive than CT scan, especially when deep seated involvement is suspected (subcortical, thalamic and brainstem). High signal lesions on T2-weighted images. Rhomboencephilitis is highly suggestive.

M-TB: Basilar meningeal enhancement combined with any degree of hydrocephalus on CT scan or MRI. MRI is more sensitive in depicting deep seated tuberculomas and spinal tuberculous arachnoiditis.

Cryptococcal: leptomeningeal enhancements, obstructive cryptococcomas are present in 10% of patients.

Toxoplasma: rarely single, more often multiple parietal, frontal lobe, thalamus and basal ganglia, ring-enhancing lesions with surrounding edema (90%) and mass effect. Immunosuppressive therapy can minimize the enhancement of these lesions. A thallium 201 SPECT scan and PET scan may differentiate between primary CNS lymphoma (high uptake) and Toxoplasmosis (normal uptake).

PML: MRI of the brain usually reveals a symmetric or asymmetric bilateral periventricular white matter lesions that show high signal intensity on T2 weighted imaging and low signal intensity in T1 (Figure 5). They usually do not enhance after gadolinium and are not surrounded by edema.

Figure 5.

High signal intensity on T2 weighted imaging associated with PML

HSV1/2: MRI is the most sensitive and specific imaging study. MRI with diffusion weighted imaging (DWI) is helpful early in the disease course. Temporal and frontal lobe abnormalities are usually unilateral.

Disseminated VZV: MRI with gadolinium can reveal a combination of ischemic and hemorrhagic lesions suggestive of vasculitis, primarily at the white-grey matter junction.

Serologic testing:

Toxoplasmosis: A negative serology IgG to Toxoplasma essentially rule out prior exposure to Toxoplasma, except in profoundly immunocompromised patients (transplant/AIDS).

Electroencephalogram (EEG):

EEG with HSV-1/2 reveals in >80% of patients, prominent intermittent high amplitude slow waves and periodic lateralized epileptiform discharges over the temporal and frontal lobes.

Brain biopsy

Brain biopsy should be attempted when:

  1. There are single or multiple brain lesions and negative IgG serology for toxoplasmosis with unrevealing LP.

  2. There is no improvement on empirical antitoxoplasma therapy after 1-2 weeks.

  3. There is clinical progression despite adequate empirical therapy.

Toxoplasmosis: Tachyzoites on Wright-Giemsa stain.

PML: significant destruction of the oligodendrocytes. The presence of JC virus is confirmed by immunostaining and electron microscopy.

HSV 1/2: Rarely requires a brain biopsy. It may show areas of mononuclear infiltrates with perivascular cuffing and necrosis. Diagnosis is obtained by HSV antigen detection (PCR, in situ DNA hybridization).

Infections with multi-organ involvement

Skin biopsy to be attempted first, if skin lesions are present, and should be obtained from nodular non-ulcerated area. Gram stain, AFB stain, modified AFB stain, fungal stain and corresponding cultures. Routine histopathology.

  • Lymph node biopsy (fine needle aspiration and preferably excisional biopsy).

  • Rapid grower mycobacterium (RGM) grow on regular media in less than one week.

  • M. marinum grows in 10-14 days.

  • M. haemophilum gows best at 30degree with Iron over 2-5 weeks.

  • MAC, M. Kansasii, M.chelonae-fortuitum, miliary M-TB usually recovered from blood cultures.

  • NTM causes granulomas: neutrophilic inflammatory infiltrates (with RGM), lymphoplasmocytic infiltrate with giant cells and fibrinous necrosis (with slow grower NTM). These granulomas can be disrupted by TNF blocker.

  • Sputum cultures (refer to pulmonary infiltrates).

  • Susceptibility testing: should be performed on all clinically significant isolates. RGM are traditionally resistant to anti TB therapy but susceptible to the following antimicrobials (minocycline, clarithromycin, azithromycin, amikacin, cefoxitin, imipinem, meropenem, doxycycline, fluoroquinolones). Multi drug resistant (MDR) M.chelonae-abcessus has been reported. (Consult with specialized centers.)

  • Direct fluorescence antibody (DFA): Scraping of lesions must be obtained before crusting and helps differentiate between HSV1/2 and VZV. It is widely available.

  • Real time PCR from clinical specimen (cutaneous lesions, BAL, CSF) rapid and sensitive test.

  • Viral culture is less sensitive than PCR with a turn around of 1-2 weeks.

Other mimickers of infections

Within other mimickers of infections (see Table IV), the following symptoms -- cutaneous vasculitis, or glomerulonephritis, are suggestive of an underlying autoimmune disease.

Other mimickers of CNS infections

Aseptic meningitis associated with headaches, cognitive impairment, stroke and brain masses are well recognized CNS complications of lupus, Wegener’s granulomatosis, polyarteritis nodosa, Behcet, sarcoidosis, lymphomatous meningitis and meningeal carcinomatosis. Acute disseminated encephalomyelitis usually follows a respiratory tract infection.

Specific confirmatory tests:

Pyogenic bacterial infection: Sputum cultures (40-60%), bronchoscopy increases the added value by 50% coupled with positive blood cultures (7-16%) and/or urinary Ag (S. pneumoniae legionella).

Legionella: The preferred tests are sputum culture on buffered charcoal yeast extract agar (BCYE) and the urinary legionella antigen.

Nocardia: Gram stain: Gram plus filamentous branching rods, modified AFB stain and positive cultures; like legionella, best on selective media such as buffered charcoal yeast extract agar (BCYE). Most routine aerobic media can support nocardia. Speciation of nocardia by PCR is more sensitive and specific than conventional methods, but is available only in research labs.

PCP: Silver stain on sputum induction (55-92%), BAL/TBBX increase sensitivity to 95-100%, some sites use PCR.

Strongyloidiasis: Larvae can be detected in sputum, pleural fluid, stools and intestinal mucosa. Two concentrated stool specimens and incubation on agar plate looking for crawling larvae (2 days). If stool exam is negative a duodeno-jejunal aspiration and ELISA serology may be helpful, although false negatives have been reported.

M-TB: nucleic acid amplification: higher sensitivity than single and or serial sputum AFB smears, but with a higher rate of false positives and false negatives in inexperienced operators. In smear positive patients, the use of direct amplification tests (DAT) - Gen-Probe MTD and AMPLCOR M.TB test - permits the confirmation of MTB within few hours with high sensitivity and specificity.

However, in negative smear sputum the sensitivity and positive predictive value drops to 48%/53% and 24%/58% respectively. A new automated Mycobacterium tuberculosis complex (MTBC) rRNA detection kit (TRCRapid M.TB), which is based on the transcription-reverse transcription concerted reaction (TRC), proved to be clinically useful for the rapid identification of MTBC in respiratory and nonrespiratory specimens and in both smear-positive and smear-negative samples.

NTM: AFB smears and cultures. Diagnostic criteria for the diagnosis of NTM disease in patients with a high pre-test probability (clinical, radiologic, after excluding fungal, M-TB and malignancy):

  • Positive sputum cultures for NTM on two separate specimen.

  • At least one positive culture result from wash obtained form BAL.

  • Positive histology from tissue obtained from TBBX or lung biopsy and + NTM culture.

  • Positive histology from tissue obtained from TBBX or lung biopsy and + NTM culture from sputum.

  • Any single positive culture for NTM obtained from a sterile site (pleural fluid, pericardial fluid).

Endemic Mycoses: Criteria for the diagnosis of endemic mycoses. Proven: host with an illness compatible with endemic fungus plus one of the following: (a) positive culture; and (b) histopathologic or direct microscopic demonstration of appropriate morphologic forms. Probable: immunosuppressed host with an illness compatible with endemic fungus plus a mycological evidence (not culture).

Histoplasmosis, acute disseminated: Urine/serum Ag ELISA positive in more than 90%. Blood culture lysis-centrifugation positive in 50-70%, or sputum positive in 60-85%, in 7-21 days. Sputum/histology have good yield in chronic pulmonary form. PCR may be better than histoplasma Ag for CNS involvement.

Coccidioidomycosis: sputum/histology stains variable (15-64%), serology high sensitivity, Serum Ag 71% sensitivity, sputum culture low sensitivity in acute pneumonia (1week).

Balstomycosis: 90% sensitivity from tissue specimens, sputum culture 66% positive but takes 4 to 6 weeks.

Penicilliosis: sputum good sensitivity, culture from blood 76%, 90% skin and 100% from bone marrow, urinary Ag is available.

Paracoccidioidomycosis: High sensitivity and specificity of sputum and histology, high sensitivity of cultures (6 weeks), multiple urinary Ag kits available with very good sensistivity.

Sporothrix: Culture of sputum and other infected material high yield. Direct microscopic examination not very sensitive.

Zygomycosis: Staining reveals broad, ribbon-like wide angled branching pauci-septate hyphae associated with tissue necrosis and angioinvasion, and it grows easily on culture media.

Respiratory viruses: Viral respiratory direct fluorescent antibody (DFA) and viral cultures may be used for Influenza A/B/H1N1, parainfluenza, adenovirus and RSV.

VZV: DFA on (CSF, BAL fluid, skin scraping), widely available, same day assay. Real time PCR more sensitive than viral cultures (1 to 2 weeks). PCR can be applied to blood/serum as well.

CMV and Aspergillus: The detection of these agents in sputum (staining, cultures) or positive CMV antigenemia (CMV PCR, PMNs staining using monoclonal antibody), coupled with the right clinical and radiological findings is supportive of probable disease and deserves empirical therapy. The confirmatory test relies on a positive histopathology showing invading pathogen. Asymptomatic shedding of CMV in bronchial secretions among immunosuppressed patients is not uncommon.

4. Specific Treatment

Pulmonary infections with respiratory compromise

Guidelines-concordant therapy is associated with improved survival in patients admitted to ICU with CAP.

Legionella: prompt initiation of antibiotics is important. Levofloxacin 750 mg IV qd plus Azithromycin 500 mg IV qd in severely ill patients. Azithromycin plus rifampin 600 mg/d is an alternative. Complete 21 days. Fluoroquinolones and azithromycin have a better intracellular penetration than erythromycin.

M-TB: the initial treatment of M-TB in immunocompromised hosts must incorporate four agents - isoniazide (INH) being the cornerstone agent, arifamycin (rifampin or rifabutin), pyrazinamide and ethambutol - for the first 2 months pending drug susceptibility testing. This is followed by a continuation phase with two fully active agents not to exceed 4-7 months, depending on the extent of lung involvement (cavitary or not) and clinical response.

MAI: azithromycin 500 mg IV qd plus amikacin 5mg/kg/d plus Ethambutol 15mg/kg/d plus rifabutin 300 mg/day, can substitute amikacin with levofolxacin 500mg/d or moxifloxacin 400 mg/d.

M. Kansasii: treatment is similar to M-TB therapy but it is given for a minimum of 12 months after the putum cultures result is negative.

Nocardia: the induction phase consists of two-drug therapy administered intravenously (sulfonamides, cephalosporine 3 rd generation, imipenem, amikacin), for 3-6 weeks or until clinical improvement is achieved, followed with an oral switch guided by antibiotic susceptibilities, usually Trimethoprim/sulfamethoxazole (10 mg/kg of the trimethoprim component in two or three doses) and/or minocycline 100 mg po qd and/or amoxicillin-clavulanate (875 mg po bid), and or extended spectrum fluroquinolones (moxifloxacin), for a total of 6-12 months.

P. jiroveci: TMP-SMX (15 mg TMP per kg per day) IV q6-q8 hours. Steroids are not recommended in non-HIV infected patients. If HIV+ with a PaO2 less than 70 mmhg, or A-a gradient greater than 35 mmHg, adjunctive corticosteroid therapy is indicated. Prednisone 40 mg po bid for 5 days, than 40 mg po qd for 5 days than 20 mg po qd for 11 days. Monitor potassium and GFR with high dose TMP-SMX. Pentamidin IV at 4 mg/kg diluted in 50-250 ml of 5% dextrose infused over on hour, daily for 14-21 days.

Hyperkalemia, hypoglycemia, hyperglycemia, cardiac arrhythmias and nephrotoxicity can occur with IV pentamidine. The combination clindamycin IV 900mg q8 + primaquine 15-30mg po qd is an acceptable alternative Caution in G6PD deficiency and patients with SLE and RA. Atovaquone suspension 5mL/750mg po bid for 21 days for mild to moderate forms.

Acute pulmonary histoplasmosis: lipososmal amphotericin B 3-5 mg/kg/d or ABLC 5 mg/kg/d or Ampho B 0.7-1.0 mg/kg/d for 1-2 weeks, then itraconazole 200 mg tid for 3 days then bid for 12 weeks.

Disseminated histopalsmosis: lipososmal amphotericin B 3-5 mg/kg/d or ABLC 5 mg/kg/d or Ampho B 0.7-1.0 mg/kg/d for 1-2 weeks, then itraconazole 200 mg tid for 3 days then bid for 12 months. Perform thoracentesis and pericardiocentesis in patients with hemodynamic and respiratory compromise.

Coccidioidomycosis: lipososmal amphotericin B 3-5 mg/kg/d or ABLC 5 mg/kg/d or Ampho B 0.6-1.0 mg/kg/d for several weeks until clinical improvement, then itraconazole or fluconazole for 1 year.

Disseminated strongyloidiasis: ivermectin 200 mcg/kg daily for 5-7 days minimum. Albendazole can be combined to ivermectin in refractory cases

CNS infections

S. pneumonia: meningeal isolates with MIC greater than or equal to 0.12 are considered resistant. Ceftriaxone or cefotaxime vancomycin plus rifampin (if dexamethasone is administered).

Cryptococcus neoformans: induction therapy with liposomal amphotericin B for 4 weeks followed by consolidation therapy with fluconazole 400-800 mg for 8 weeks and maintenance therapy if immunosuppressive therapy reinstituted 200 mg/day.

M-TB: same as pulmonary TB; an initial four drugs regimen for 2 months promoting rapid killing, followed by at least a 10 month continuation phase with two agents based on initial response and drug sentivities of the isolate. Dexamethasone is recommended in patients with acute encephalitis plus high intracranial pressure and intracerebral tuberculoma with edema and neurologic deficit, and in those patients who mount a paradoxical neurologic deterioration in the setting of immune reconstitution.

Listeria monocytogenes: ampicillin 2 gr IV q4hrs for 21 days plus Gentamicin 5mg/kd/day for the first week for synergy, or Trimethoprim-sulfamethoxazole (20 mg/kg per day in 4 divided doses) in patients allergic to penicillin. Treatment should be prolonged to 6 weeks if there is cerebral involvement.

HSV-1/2 encephalitis: acyclovir 10 mg/kg Q8hrs for 14-21 days.

PML: discontinue immunosuppressive drugs. No specific treatment. Cytarabine 2 mg/kg for five days appear to stabilize the neurologic and functional status in some patients. Mirtazapine may help with symptoms. Plasma exchange for patients with multiple sclerosis on natalizumab. Short-term steroids may be beneficial for patients with inflammatory PML (evidence of brain edema).

CNS histoplasmosis: liposomal amphotericin B 5 mg/kg/d for a total of 175 mg/kg for a total of 4-6 weeks, then itraconazole 200 mg tid for 3 days, then bid for at least 12 months. Voriconazole effective for itraconazole failures.

Coccidioidomycosis meningitis: fluconazole 400-1000 mg qd or voriconazole 6 mg/kg/q12 for several weeks followed by oral fluconazole or voriconazole indefinitely.

Nocardiosis: there is a lack of randomized, controlled studies. Usually 4-12 weeks of IV therapy (average 6 weeks) of trimethoprim-sulfamethoxazole (TMX-SMX) ,15 mg/kg IV of the trimethoprim component administered in 2-4 doses plus ceftriaxone 2 gms IV q 12 h or cefotaxime 2 gms IV q8h or imipenem 500 mg IV q6h until a response is achieved, followed with a switch to a combination of two oral agents that the isolate is susceptible to, and complete a total course of 12 months.

Infections with multi-organ involvement

  • Empirical therapy should be guided by the most likely diagnosis.

  • Patients with severe disease due to an RMG: Specific therapy should be guided by antibiotic susceptibility. Maintain therapy with a dual combination of IV antibiotics for 2-6 weeks (imipinem 500mg IV q6hr or meropenem 1 gr IV bid plus amikacin IV 7.5 mg/kg/q12 or tobramycin IV 5 mg/kg/day) in addition to two oral agents (macrolide + quinolone or minocycline100 mg po qd). Convert to an oral combination with at least two agents, guided by antibiotic susceptibility for several months (no less than 6 months in immunocompromised patients). Linezolid 600 mg po bid, and Tigecycline 100 mg IV once then 50mg IV qd, can play a role in patients with MDR RGM.

  • M. kansasii: same as pulmonary treatment.

  • M. mrinum: treat with clarithromycin 500 mg po bid plus rifampin600 mg po qd plus ethambutol 15-20 mg/kg/day for 6 months.

  • M. hemophilum: treat with clarithromycin 500 mg po bid plus rifampin600 mg/d plus quinolone. (Treatment of M. Hemophilum consists of a combination of three antibiotics, with Moxi better than levofloxacin which is equivalent to ciproflo.)

  • Discontinue immunosuppressive therapy.

  • Surgical therapy is indicated for removal of foreign body, incision and drainage of an abscess, necrotic tissue, and refractory deep seated infection (bone involvement). Removal of an infected device is almost always necessary for cure.

  • VZV/DH, CNS involvement and/or ophthalmic involvement: Acyclovir 10 mg/kg three times a day for the first 5-7days. Switch to oral valacyclovir 1gr po tid or famciclovir 500 mg po tid for two extra weeks.

  • Routine use of corticosteroid is not recommended.

  • Aggressive analgesia for associated neuralgia (opioids, gabapentin, pregabalin, amytriptilline).

5. Disease monitoring, follow-up and disposition

Pulmonary infections with respiratory compromise

Clinical improvement of CAP pneumonia (resolution of fever, decrease respiratory rate <24 breaths/mn and systolic BP >90mm Hg, occur within 3-4 days after initiation of proper therapy. If no improvement observed after 72 hours, patient is considered non-responder.

Radiologic response lags behind clinical improvement:

  • 56% improvement and 25% resolution at day 7.

  • 53% resolution at day 28.

  • It takes 4-6 weeks to note a significant resolution of infiltrates on CXR.

  • It may take 12 weeks for complete resolution in older patients and/or patients with chronic architectural parenchymal disease.

P. jiroveci: response to therapy becomes notable in 4-5 days. Adding an extra medication increases the toxicity without improving the chances of cure.

Legionella: improves within 3-5 days after initiation of appropriate antibiotics.

Superinfection with other respiratory pathogens occur in 10% of cases of legionella.

Urinary histoplasma: antigen level may be useful to monitor response to therapy every three months. An increase of 2 UI or more predicts relapse.

M-TB, Nocardiosis: see CNS treatment.

Disseminated strongyloidiasis: daily monitoring of larval burden in stools. Decreasing serologic titers of strongyloides on ELISA repeated 3-6 months after therapy may be useful.

The non-responding patient: suspect a complicated pneumonia (post-obstructive pneumonia, empyema, abscess) or atypical pathogen or resistant pathogen or another superimposed process (i.e. congestive heart failure, underlying rheumatic disease, bronchiolitis, obliterans organizing pneumonia (BOOP). More imaging studies and invasive tests warranted.

CNS infections

Bacterial meningitis, HSV-1/2 encephalitis respond to therapy after few days.

Toxoplasma responds to therapy after one to two weeks.

Cryptococcal meningitis may necessitate daily lumbar punctures, lumbar drains and sometimes ventriculoperitoneal shunts to minimize the intracranial pressure. Repeating lumbar pressure plus opening pressure after 2 weeks of adequate treatment is warranted in patients who did not improve.

Monitor for signs of dissemination (skin lesions, lymph nodes and others).

Monitor for drug toxicity: vestibular toxicity with aminoglycosides, hematologic toxicity with linezolid, sulfamides, vancomycin and beta lactams, renal toxicity with sulfamides, penicillins M, and aminoglycosides, liver toxicity with isoniazide and rifampin, neurologic toxicity with linezolid, muscle toxicity with daptomycin.

Pathophysiology

Pulmonary infections with respiratory compromise

The vast majority of granulomatous infections are initially acquired through inhalation and may go unrecognized and remain quiescent for years. There is an increased risk of reactivation following immunosuppression associated with a higher likelihood of dissemination from the initial pulmonary focus to the skin, skeleton, CNS and other organs.

Both reactivation of latent disease and de novo infections with histoplasmosis and coccidioidomycosis have been reported, especially after inhalation of a large inoculum in endemic areas.

P. jiroveci follows intensification of cell-mediated immunosuppressive therapy. It remains the most common cause of opportunistic lung infection in patients with rheumatic diseases.

Hyperinfection and dissemination of strongyloides larvae is triggered by the amplification of the auto infective cycle during T-cell suppression. Massive amount of larvae cross the intestinal wall, carrying Gram negative and yeast into the bloodstream (polymicrobial bloodstream infections), and invade hematogenously different organs, causing acute inflammation and antigen stimulation.

Legionella transmission occurs via inhalation of contaminated aerosolized mist from water sources (cooling towers, showers, whirlpool). Person to person transmission has not been documented. Nosocomial cases have been reported. Risk factors for infection: advanced age, smoking, chronic heart or lung disease.

CNS infections

Hematogenous spread is the most common mechanism of seeding (pyogenic bacteria, M-TB, listeria, toxoplasma, endemic fungi, NTM, Cryptococcus and viruses).

Direct extension from a contiguous site such as mastoiditis, sinusitis and chronic otitis media (brain abscess) is the second most common mechanism

Neuronal spread comes third (HSV1/2).

Invading pathogens breach the blood-brain barrier (BBB).

Inflammatory response mediated by TNF alpha, IL-1B, IL-6, IL-8, IL-10.

Profound dysregulation of the cerebral microcirculation, disruption of the BBB, increased permeability, vasogenic edema, cytotoxic edema, obstruction of CSF outflow at arachnoid villi.

Increased intracerebral pressure, cerebral hypoperfusion and ultimately herniation and brain cell death.

Reactivation of latent infections that occur primarily within the first 90 days from the initiation of TNF blocker.

Listeria, a food-born pathogen, accesses systemic circulation through the GI tract and spreads to the CNS hematogenously. Brain abscess occurs in 10% of CNS infections: Thalamus, pons and medulla. Protection is mediated by lymphocytes and macrophages and by IL-18.

PML: reactivation of JC virus, which affects the oligodendrocytes, produces demyelination, primarily in the subcortical white matter. Infected oligodendrocytes have an enlarged amphophilic nuclei, with reactive gliosis and no inflammatory infiltrates.

Infections with multi-organ involvement

NTM enters the host’s system by inhalation, ingestion (MAC) or direct skin invasion.

Herpes Zoster (HZ): the estimated lifetime attack rate is 30%. It is a reactivation of latent varicella zoster virus infection. Related to a decline in VZV-specific cell mediated immunity and presents as a neurocutaneous disease. The dorsal spinal ganglion exhibits a significant hemmorhagic inflammation which can extend centrally to the spinal cord and leptomeninges and peripherally along sensory axons to the corresponding dermatome. Subsequent dermatomal or disseminated eruption plus acute herpetic neuralgia will follow.

Reactivation of CMV can occur at anytime following intense cell-mediated immunosuppression. Although more common in post transplant patients, it has been seen in patients on antilymphocytes therapy, especially following an acute illness.

Many pathogens with predilection to the lungs and CNS can disseminate and involve other organs. Always monitor for skin lesions, lymph nodes, bone marrow, hepatosplenic, ocular and other organ involvement.

Epidemiology

Pulmonary infections with respiratory compromise

CAP associated with common pyogenic bacteria remain the most frequently encountered respiratory tract infections.

Granulomatous infections are more common among patients treated with TNF blockers, preferentially infiliximab. The vast majority of atypical infections have been reported with combination therapy of TNF blocker and other immunosuppressive agents, particularly prednisone or methotrexate.

Reactivation of latent M-TB occurs after a median of 12 weeks post initiation of infliximab infusion. The relative risk of M-TB in patients with RA treated with TNF blocker is eight-fold higher than in patients without RA and M-TB occurs at a rate of 54 events/100.000 patients with infliximab vs 28 events/100,000 with etanercept vs 6.4/10,000 in the general U.S. population.

Fungal infections associated with infliximab occurred within the first 55 days of therapy, whereas those associated with etanercept occurred within a median of 144 days.

Histoplasmosis among patients treated with Infliximab is 17/100,000 patients vs 3/100,000 among patients treated with etanercept.

Coccidioidomycosis has been reported in association with TNF blocker at a rate of 11/100,000 patients with infliximab and 1/100,000 with etanercept. Cryptococcosis estimated at a rate of 9/100,000pts.

-The rate of NTM in the U.S. has been estimated at between nine cases/100,000 patients with infliximab and six cases per/100,000 patients with etanercept. MAC is the most common agent. M. abscessus and M. fortuitum are the most common RGM accounting for pneumonias. M. abscessus account for 80% among RGM, vs 15% M. fortuitum.

Aspergillosis and invasive candidiasis have been reported at a rate of 7-8 cases per 100,000 patients.

The mean time between Infliximab infusion and P. jiroveci emergence is 21 days plus or minus 18 days.

CNS infections

CNS histoplasmosis is 3-fold more common than tuberculosis in patients receiving TNF blockers.

Listeria is a food-borne disease (coleslaw, blue cheese, milk, corn, deli meat). 70% of nonperinatal infections occur in immunocompromised patients. Bacteremia and meningitis has been reported at higher rate with infliximab (9/100,000 pts) than etanerecept (1/100,000 pts).

HSV-1 encephalitis is the most common form of sporadic encephalitis worldwide. Cryptococcus is ubiquitous.

Histoplasmosis, coccidioidomycosis are endemic in certain areas (see define epidemiologic circumstances surrounding onset of disease).

Infections with multi-organ involvement

NTM are ubiquitous, found in wet soil, water, house dust, milk, food products and wild animals.

NTM reported in 11/100,000 patients treated with infliximab vs 6/100,000 in patients treated with etanercept.

The number of NTM infections in the U.S. exceeds M-TB infections. Most cases were MAI, but cases with M. chelonae, M abscessus, M. marinum, M. fortuitum, M. haemophilum, M. kansasii and M. scrofulaceum have been reported. The lungs followed by skin are the main port of entry of infections. If untreated NTM can disseminate to involve other organs.

M. fortuitum-chelonae infections usually follow cosmetic surgery or penetrating trauma.

Disseminated MAC infection is rarely associated with skin lesions. More than 70% of adults have been exposed to MAC.

M. kansasii is mainly recovered from tap water as opposed to soil and natural water supplies.

M. abscessus, the most pathogenic of RGM, affects the lung in 80% of cases and can disseminate and seed skin. Direct inoculation into the skin is possible.

Most disseminated endemic fungal infection were encountered among patients receiving TNF blockers in combination with additional immunosuppressive therapy. Although reactivation is suspected, reinfection of patients with weakened cell-mediated immunity followed by dissemination may be an important mechanism in endemic areas.

Primary VZV usually occurs during childhood. The incidence declined after introduction of vaccine. It is highly contagious within households (attack rates >90% among susceptible adults). Disseminated VZV is more prevalent among transplant and leukemia patients compared to other immunosuppressed hosts. The incidence is highest with patients on TNF blocker: 9.7/1,000 patient-years with Infliximab and 3.6/1,000 patient-year with etanercept. Other risk factors include older age, prednisone use, TNF blocker plus DMARDs and the presence of other co morbidities (diabetes, CHF, CRF, liver disease). Delayed onset of disseminated HZ infection has been seen after rituximab use.

CMV: reactivation of latent disease in patients with depressed cell mediated immunity presenting with pancytopenia, colitis, retinitis, esophagitis, encephalitis and pneumonitis.

Prognosis

Pulmonary infections with respiratory compromise

Legionella: Mortality varies between 12-18% in immunosuppressed patients. Progressive respiratory failure carries a poor prognosis.

Pneumocystis is a common cause of respiratory failure leading to intubation. Mortality is 30-50% with P. jiroveci, and up to 60% in intubated patients, especially with pneumothorax. It carries a worse prognosis than in HIV infected patients.

Disseminated histoplasmosis: untreated is fatal. Cure rate of meningitis are 50% with a high rate of relapse.

Disseminated coccidioidomycosis: mortality among patients above 65 is high. Most patients do well with therapy.

Disseminated Strongyloidiasis mortality can be a s high as 70-90%.

CNS infections

Listeria: The mortality rate associated with listeria is elevated. The highest rate seen among patients with sepsis and brain abscesses, and varies between 22-32%; sequelae are not uncommon among patients recovering from rhomboencephalitis.

Coccidioidomycosis: the most common complication is hydrocephalus (30%), which carries a mortality rate of 40%. Thrombosis of intracranial vessels causes strokes in 10%.

Cryptococcal meningitis responds to adequate antifungal therapy in the majority of cases.

HSV-1/2 encephalitis carries a mortality of 20-30% despite appropriate therapy. Long term followup of treated patients may show seizure disorder, and different degrees of neuropsychiatric and neurocognitive dysfunction.

PML: usually fatal, with a median survival of 3 months; however some patients survived with neurologic sequelae.

Infections with multi-organ involvement

Mortality is high with disseminated endemic fungi, M-TB, NTM, strongyloidiasis and aspergillosis.

Mortality is high with pneumonitis caused by VZV/DH. DH-induced acute retinal necrosis could be devastating. Only 20% of patients retained useful vision at two months followup. The risk of post herpetic neuralgia doesn’t seem to be increased in immunosuppressed patients.

Special considerations for nursing and allied health professionals.

NA

What's the evidence?

We would like to acknowledge Mark J. DiNubile M.D. (Merck Research Labs) for reviewing this chapter.

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(This roadmap article reviews in depth the initial assessment of the immunocompromised host admitted to ICU, the common and altered expression of their disease, and the need for an aggressive diagnostic work-up and early empirical therapy.)

Martin-Mola, E, Balsa, A. "Infectious complications of biologic agents". Rheum Dis Clin North Am. vol. 35. 2009 Feb. pp. 183-99.

(Comprehensive review of infections associated with TNF antagonists and non-TNF agents among patients with primarily rheumatoid arthritis. Data is derived from several registries, meta-analysis and several randomized controlled trials.)

Kim, SY, Solomon, DH. "Tumor necrosis factor blockade and the risk of viral infection". Nat Rev Rheumatol. vol. 6. 2010 Mar. pp. 165-74.

Bongartz, T, Sutton, AJ, Sweeting, MJ, Buchan, I, Matteson, EL, Montori, V. "Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials". JAMA. vol. 295. 2006 Jun 7. pp. 2482-85.

(This systematic extensive review and meta-analysis reveals a high rate of serious infections and a dose dependent increased risk of malignancies associated with TNF blockers among patients with rheumatoid arthritis. Non-granulomatous infections were more prevalent.)

Salvana, EM, Salata, RA. "Infectious complications associated with monoclonal antibodies and related small molecules". Clin Microbiol Rev. vol. 22. 2009 Apr. pp. 274-90.

Koo, S, Marty, FM, Baden, LR. "Infectious complications associated with immunomodulating biologic agents". Infect Dis Clin North Am. vol. 24. 2010 Jun. pp. 285-306.

(This article reviews the immunopathogenesis associated with immunomodulating biologic agents leading to infectious complications and highlights the epidemiologic scope of these infections.)

Campbell, L, Chen, C, Bhagat, SS, Parker, RA, Ostör, AJ. "Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials". Rheumatology (Oxford). 2010 Nov 14.

Mandell, LA, Wunderink, RG, Anzueto, A, Bartlett, JG, Campbell, GD. "Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults". Clin Infect Dis. vol. 44. 2007 Mar 1. pp. S27-72.

Schmidt-Hieber, M, Zweigner, J, Uharek, L, Blau, IW, Thiel, E. "Central nervous system infections in immunocompromised patients: update on diagnostics and therapy". Leuk Lymphoma. vol. 50. 2009 Jan. pp. 24-36.

Griffith, DE, Aksamit, T, Brown-Elliott, BA, Catanzaro, A, Daley, C. "An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America". Am J Respir Crit Care Med. vol. 175. 2007 Apr 1. pp. 744-5.

De Pauw, B, Walsh, TJ, Donnelly, JP, Stevens, DA, Edwards, JE. "Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group". Clin Infect Dis. vol. 46. 2008 Jun 15. pp. 1813-21.

Clifford, DB, De Luca, A, Simpson, DM, Arendt, G, Giovannoni, G. "Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases". Lancet Neurol. vol. 9. 2010 May. pp. 463-46.

(In this post-marketing analysis of 28 cases of PML associated with natalizumab, the presenting symptoms, MRI and LP findings are reviewed in detail. Eight of 28 patients had a fatal outcome. PML risk of reactivation increased with duration of exposure to natalizumab mainly after year 2.)

Perfect, JR, Dismukes, WE, Dromer, F, Goldman, DL, Graybill, JR. "Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america". Clin Infect Dis. vol. 50. 2010 Feb 1. pp. 291-322.

Takeuchi, T, Tatsuki, Y, Nogami, Y, Ishiguro, N, Tanaka, Y. "Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis". Ann Rheum Dis. vol. 67. 2008 Feb. pp. 189-94.

Wallis, RS, Ehlers, S. "Tumor necrosis factor and granuloma biology: explaining the differential infection risk of etanercept and infliximab". Semin Arthritis Rheum. vol. 34. 2005 Apr. pp. 34-8.

Harris, J, Keane, J. "How tumour necrosis factor blockers interfere with tuberculosis immunity". Clin Exp Immunol. vol. 161. 2010 Jul 1. pp. 1-9.

Weinblatt, ME, Bathon, JM, Kremer, JM, Fleischmann, RM, Schiff, MH. "Safety and efficacy of etanercept beyond 10 years of therapy in North American patients with early and long-standing rheumatoid arthritis". Arthritis Care Res (Hoboken). 2010 Oct 18.

Ehlers, S. "Tumor necrosis factor and its blockade in granulomatous infections: differential modes of action of infliximab and etanercept?". Clin Infect Dis. vol. 41. 2005 Aug 1. pp. S199-203.

Taiwo, B, Glassroth, J. "Nontuberculous mycobacterial lung diseases". Infect Dis Clin North Am. vol. 24. 2010 Sep. pp. 769-89.

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