- Rapid Reference 🚀
- Preamble: what this chapter is about
- Clinical presentation
- Diagnostic panel
- Approach to treatment failure
- Extrapulmonary complications
- Virology of influenza
- Questions & Discussions
severe influenza checklist ✅
diagnostic tests (more)
- COVID PCR.
- Nares PCR for MRSA.
- Blood cultures.
- Sputum gram stain & culture.
- Ferritin, liver function tests.
- Ultrasound if needed to exclude effusion.
- CT scan if diagnostic uncertainty (e.g., vs PE or opportunistic infection).
resuscitation & respiratory support (more)
- Fluid conservative resuscitation – DO NOT bolus 30 cc/kg fluid.
- Consider early high-flow nasal cannula for dyspnea/tachypnea.
- Oseltamivir 75 mg BID (or IV peramivir if NPO).
- Clarithromycin 500 mg BID (azithromycin if clarithromycin unavailable or ⬆️QT).
- Beta-lactam until bacterial pneumonia excluded (e.g., ceftriaxone, piperacillin-tazobactam, or cefepime).
- Linezolid 600 mg PO/IV q12hr if post-flu MRSA pneumonia suspected.
- Steroid is neither routinely indicated, nor contraindicated.
- Steroid should be used if indicated for another reason (e.g., COPD/asthma, adrenal insufficiency, or virus-associated hemophagocytic syndrome 📖).
what this chapter is about
This chapter is about the patient presenting with influenza pneumonia and respiratory failure requiring critical care.
Influenza is one of the most dangerous epidemic infectious diseases in modern history (e.g., causing ~75 million deaths in the 1918 H1N1 influenza pandemic). Different strains of influenza return annually, claiming ~25,000 lives per year in the United States alone. Given that our healthcare systems routinely run near maximal capacity in the winter, it's only a matter of time until influenza out-strips available resources.
- Initial flu-like clinical syndrome occurs (e.g., fever, sore throat, cough, arthralgias, chills, headache, and sometimes diarrhea).
- This worsens with the development of dyspnea.
- Some sputum production may occur, which can be bloody.
- This can look a lot like uncomplicated influenza; hypoxemia and tachypnea are the key distinguishing features.
- Chest ultrasonography
- Usually shows an ARDS-type pattern. This may include patchy areas of B-lines intermixed with areas of A-lines, areas of dense subpulmonic consolidation (small patches of severely diseased lung in contact with the pleura), and a thick/ragged pleural line.(18442425)
- Chest ultrasonography does not allow differentiation from other causes of ARDS (e.g., COVID).
- Chest X-ray
- Will often show patchy bilateral infiltrates (example above).
- Films may not appear impressive; they will often underestimate how ill the patient is.
- CT scan
- Common features include ground glass opacities and multi-focal areas of consolidation.
- Cavitation or lobar consolidation or substantial pleural effusion suggests an alternative or additional diagnosis (e.g., superimposed bacterial pneumonia).
- Influenza alters the host immune system, predisposing to bacterial pneumonia. The risk of bacterial pneumonia peaks 1-2 weeks after infection, but can persist for months. The causes are likely multifactorial (e.g., disruption of respiratory epithelia, altered cytokine milieu). Such pneumonias are classically associated with infection by Streptococcus pneumoniae, group A Streptococcus, or Staphylococcus aureus (including MRSA).
- Coinfection can present in different ways, for example:
- Patient may present to the hospital with a post-influenza bacterial pneumonia.
- Patient may present to the hospital with a pure influenza pneumonia, with subsequent development of a nosocomial bacterial/fungal pneumonia.
clinical features suggestive of post-influenza bacterial pneumonia may include:
- Biphasic illness: Patient develops influenza, starts getting better for a few days, then deteriorates.
- Copious sputum production (not generally a feature of influenza pneumonia).
- Radiographic features suggestive of bacterial pneumonia (e.g., dense lobar consolidation or cavitation)
- Retrospective series have found that invasive aspergillosis complicates ~7-19% of ICU patients with influenza. Given challenges in making the diagnosis, it's possible that some studies have underestimated this. Overall, it might be reasonable to guess that roughly ~5-10% of influenza-related ICU deaths may be precipitated by Aspergillus superinfection.
- Risk factors may include:
- H1N1 influenza.
- More severe influenza.
- Underlying structural lung disease (severe COPD or bronchiectasis).
- Aspergillus infection may be diagnosed relatively soon in the ICU course (a median of 3-5 days after admission).
investigations to consider 📖
- Less invasive:
- Chest CT scan (however, there may be less likelihood of developing cavitation among immunocompetent patients with influenza).(32572532)
- Serum levels of galactomannan and beta-D-glucan.
- Fungal cultures of sputum and/or tracheal aspirate.
- Evaluation of bronchi for visible evidence of fungal tracheobronchitis.
- Bronchoalveolar lavage (BAL) for culture, fungal stain, and galactomannan level.
- Sorting out colonization versus invasive infection can be challenging. Ultimately this requires considering the totality of imaging, clinical, and laboratory data.
- Below is one proposal for a case definition of invasive aspergillosis within the context of severe influenza.(32572532)
diagnostic studies for influenza
- Nasopharyngeal PCR is the front-line test, with ~90% sensitivity. However, if swabbing isn't performed deeply enough then the sensitivity may be lower.
- If a nasopharyngeal PCR is negative and yet suspicion for influenza remains:
- For a non-intubated patient, it may be reasonable to repeat the nasopharyngeal PCR (especially if the sample quality of the first test is unclear). Sputum may also be tested using PCR.
- For an intubated patient, tracheal aspirate or bronchoalveolar lavage fluid should be sent for PCR.(30566567) This is arguably the gold-standard investigation. Viral replication in the lung may continue after the virus is no longer detectable in the upper respiratory tract, especially with strain H1N1pdm09.(31189475)
- Expanded PCR testing for multiple viruses should be considered (e.g., COVID, influenza, RSV, and metapneumovirus). Other viruses may mimic influenza pneumonia.
other studies to evaluate for alternative (or superimposed) diagnoses:
- Blood cultures.
- Sputum for gram stain & culture.
- Nares swab for MRSA PCR.
- Nasopharyngeal PCR for COVID.
- Urine streptococcal & legionella antigens.
- Procalcitonin: Influenza doesn't generally increase procalcitonin. Thus, procalcitonin may be used to exclude bacterial pneumonia here, the same way it may be used other contexts.(28159162, 31912206)
- Ferritin, liver function tests.
- Chest X-ray.
- Chest CT scan may be considered (e.g., if chest X-ray suggests nodular infiltrates or cavitation).
avoid large-volume resuscitation
- Patients with influenza pneumonia usually die from ARDS, which may be aggravated by large-volume resuscitation.
- Whenever reasonable, fluid administration should be avoided. For example:
- For a mildly hypotensive patient, low-dose vasopressors may be preferable to large-volume resuscitation.
- For a normotensive patient, DO NOT give the Surviving Sepsis Campaign mandated 30 cc/kg fluid bolus.
- The value of measuring lactate is dubious and shouldn't be used as a stimulus to give fluid.🌊 Lactate may be mildly elevated due to an endogenous sympathetic response from the increased work of breathing and anxiety – fluid administration will only make this worse.
Bacterial superinfection occurs in about a third of patients with influenza and respiratory failure. It's generally impossible to immediately differentiate influenza pneumonia from bacterial pneumonia upon clinical grounds (influenza PCR may be positive in both scenarios). Therefore, empirical coverage of bacterial co-infection should be provided initially (until microbiologic studies return).(30566567). The most common bacterial pathogens are Streptococcus pneumoniae or Staphylococcus aureus, with less common offenders being Haemophilus influenzae, Streptococcus pyogenes, or Pseudomonas aeruginosa.(31313681).
#1) macrolide therapy
- Macrolide therapy plays up to three roles here:
- Clarithromycin 💉 may be the preferred agent due to its superior activity against influenza. The usual dose is 500 mg twice daily for patients with GFR >30 ml/min.
- Azithromycin 💉 should be used for patients who cannot receive oral medications (with a usual dose of 500 mg IV daily).
- A negative procalcitonin cannot exclude atypical pneumonia. In some situations, it may be reasonable to continue a course of therapy for atypical pneumonia even if the procalcitonin is negative.
- A beta-lactam should be used to cover typical bacterial pathogens initially (usually ceftriaxone 💉 1 gram IV daily).
- An antipseudomonal beta-lactam (piperacillin-tazobactam 💉 or cefepime 💉) may be used in patients with risk factors for pseudomonas, for example:
- Septic shock due to pneumonia.
- Structural lung disease (e.g., bronchiectasis or advanced COPD with frequent exacerbations).
- Broad-spectrum antibiotics for >7 days within past month.
- Hospitalization for >1 day within past three months.
- Immunocompromise (e.g., chemotherapy, chronic use of >10 mg prednisone daily).
- Nursing home resident with poor functional status.
- The need for ongoing beta-lactam therapy may be determined based on procalcitonin and sputum culture results. For uncomplicated influenza pneumonia, the beta-lactam can generally be discontinued within <48 hours.
#3) MRSA coverage
- MRSA is classically associated with post-flu bacterial pneumonia. MRSA coverage should be used if the clinical history suggests a post-influenza bacterial pneumonia.(30566567)
- Linezolid 💉 is arguably the best agent here, given evidence of superiority for MRSA pneumonia and reduced risk of nephrotoxicity.(22247123, 25355172, 25066668, 27208687, 24238896, 26382940, 24916853, 24420846, 23568605, 21163725, 18719064) If there are contraindications to linezolid, vancomycin 💉 may be used.
- MRSA coverage may be discontinued if procalcitonin is negative (<0.5 ng/ml) or if no laboratory evidence of MRSA emerges (e.g., nares PCR, blood, and sputum cultures are negative). MRSA therapy should generally be stopped within two days, unless there is some laboratory evidence of MRSA. (More on the role of MRSA coverage in pneumonia here).
1st line = enteral oseltamivir 💊
- Oseltamivir is an oral neuraminidase inhibitor. Its utility has been greatly overblown. Nonetheless, critically ill patients with known influenza pneumonia should receive oseltamivir, regardless of illness duration (75 mg PO twice daily, with dose reduction in renal failure).(30566567)
- Side-effects of oseltamivir include nausea, vomiting, delirium, and very rarely Stevens-Johnson syndrome.
- Safe and recommended in pregnancy.(32068576)
- Standard dose: 75 mg PO BID.
- GFR 30-60 ml/min: 30 mg PO BID.
- GFR 10-30 ml/min: 30 mg PO daily.
- GFR <10 ml/min and not undergoing dialysis: Not recommended or studied.
- Hemodialysis: 30 mg PO loading dose, then 30 mg after each hemodialysis session.
- Duration: A minimum of five days of therapy should be provided. 10-day courses of therapy may be considered in critically ill patients, in whom influenza viral replication may be protracted.(30566567)
2nd line = IV peramivir 💊
- Peramivir is an intravenous neuraminidase inhibitor (with the same mechanism of action as oseltamivir). Peramivir is preferred therapy for patients without enteral access, who cannot receive oseltamivir.
- Available data suggest that oseltamivir and peramivir may have similar efficacy (although this hasn't been studied in critical illness).
- Among outpatients, a single dose of 600 mg IV is used (since peramivir has a long 20-hour half-life). For critically ill patients, consideration may be given to administer a multi-day regimen (but the optimal dosing is unknown).(30566567)
dubious role: zanamivir 💊
- Zanamivir is an neuraminidase inhibitor which is usually administered via in inhaled route (although an intravenous formulation is available for compassionate use). It may have an advantage against strains of influenza which are resistant to oseltamivir and peramivir. However, currently oseltamivir resistance isn't a problem (with ~98% sensitivity).(30172033)
- Inhaled zanamivir may cause bronchospasm. This is contraindicated among intubated patients because the lactose powder formulation may cause ventilator filter obstruction.(30566567)
dubious role: baloxavir 💊
- Baloxivir inhibits influenza cap-dependent endonuclease, thereby blocking initiation of viral mRNA synthesis.
- Recently baloxavir was demonstrated to be effective among outpatients.(30184455)
- Baloxavir is not widely available. There is currently no evidence regarding its use in ICU.
high-flow nasal cannula (HFNC) and/or CPAP/BiPAP 📖
- The optimal mode of respiratory support for influenza pneumonia is unknown currently.
- Early institution of support might prevent the development of diaphragmatic fatigue with eventual frank respiratory failure.
- HFNC is safer for patients at risk of emesis. It may be better tolerated by some patients, especially those with claustrophobia.
- BiPAP or CPAP may offer the following advantages:
- Especially useful for patients with comorbid COPD or asthma (who are exacerbating an exacerbation of airway obstruction).
- Provision of higher levels of positive airway pressure may help recruit lung tissue (especially among patients with morbid obesity).
- In the absence of definitive evidence, it may be reasonable to trial different devices and determine which suits an individual patient best. Some patients may benefit from alternating BiPAP and HFNC (e.g., BiPAP may support the work of breathing better, but periods of HFNC may be needed to promote secretion clearance).
- Intubation may be indicated for progressive desaturation or worsening dyspnea, despite optimization of noninvasive respiratory support.
- Influenza can impair surfactant production in animal models, thereby leading to lung derecruitment.(27836900) This suggests that patients may benefit from higher mean airway pressures (e.g., higher levels of PEEP, or APRV).(21593048, 30140503)
- There is no high-quality evidence regarding the use of steroid in influenza.
- Numerous retrospective studies have correlated the use of steroid with poor outcomes.(21107529, 21471082, 21810744) However, this doesn't prove a causal relationship. Steroid administration serves as a marker of sicker patients (causing confounding by indication). Attempts to perform adjusted regression analyses to eliminate confounding variables have yielded conflicting results.(32068576)
- Parallels between severe influenza and COVID-19 might imply that there is utility of steroid for viral pneumonia (including influenza). Most notably, it was incorrectly believed that steroid was detrimental in COVID, until this was properly tested in a prospective RCT by the RECOVERY trial (which demonstrated a mortality benefit from dexamethasone).
- For now, this issue remains unresolved. Routine administration of steroid to patients with severe influenza is not recommended by guidelines.(30172033) Potential indications for steroid might include:
- Virus-associated hemophagocytic syndrome.📖
- Another indication for steroid (e.g., exacerbation of comorbid asthma or COPD).
- Naproxen has in vitro activity which prevents replication of H1N1 and H3N2 influenza.(23459490)
- It's possible that the combination of naproxen with clarithromycin and oseltamivir could create an effective triple-therapy against influenza. One single-center unblinded RCT found that triple therapy improved mortality compared to monotherapy with oseltamivir alone.(27884765)
- Their cocktail utilized was oseltamivir 75 mg BID, naproxen 200 mg BID, and clarithromycin 500 mg BID. Naproxen and clarithromycin were used only for the first two days, whereas oseltamivir was continued for a five-day course.
- The use of naproxen for influenza remains unclear. Naproxen might possibly be considered if the following criteria are met:
- Symptom duration less than four days.
- Laboratory confirmed influenza (ideally H3N2 or H1N1 strains).
- Pulmonary infiltrates on chest X-ray or CT scan.
- Creatinine clearance >30 ml/min, no acute kidney injury or hypoperfusion, and no other nephrotoxic medications.
- If naproxen is used, it should be limited to a two-day course (four tablets in total).
virus-associated hemophatocytic syndrome (VAHS)
what is VAHS ?
- Hemophagocytic lymphohistiocytosis (HLH) is a state of immune hyperactivation wherein macrophages phagocytize blood cells (including erythrocytes and neutrophils).📖 It can be caused by a wide variety of underlying disorders (e.g., malignancy, autoimmune disorders, or hematologic malignancy).
- Virus-associated hemophagocytic syndrome (VAHS) refers to hemophagocytic lymphohistiocytosis due to viral infection. 🌊
- VAHS appears to occur predominantly with H1N1 and H5N1 types, but it can occur with other types as well (H3N2).(16785288, 16530581)
- One prospective case series detected VAHS in 1/3 of critically ill adults with H1N1 influenza.(21366922) Among autopsies of patients who died from H1N1 influenza, histological evidence of hemophagocytosis is present in 68/87 cases (78%).(20551263, 21724431, 26597256)
- Usually VAHS seems to be a delayed complication, arising ~1-2 weeks after ICU admission. However, several reports describe patients presenting to the hospital with VAHS present upon admission.(17106167, 21722406, 22286408)
- Diagnosis of VAHS is challenging, because it overlaps with the features of severe infection. Features suggesting VAHS include the following:
- Cytopenias in at least two cell lines (anemia, thrombocytopenia, neutropenia).
- Fibrinogen <150 mg/dL, disseminated intravascular coagulation.
- Ferritin >>500 ng/mL.
- Lactate dehydrogenase (LDH) elevation >1,000 U/L.
- Liver function test abnormalities (may be severe).
- Hypertriglyceridemia (>265 mg/dL or >3 mM/L).
- In suspect cases, serial laboratory monitoring may facilitate prompt diagnosis (e.g., ferritin, triglycerides, fibrinogen, and liver function tests).
- The traditional definition of HLH is based upon the HLH-2004 criteria shown above. HLH-2004 criteria are unhelpful in critically ill adults for several reasons:(28631531)
- These criteria were developed for use in a clinical trial of pediatric HLH.
- They rely on tests which are impossible to obtain rapidly (or ever).
- By the time HLH-2004 criteria are officially “positive” the patient may be moribund and beyond the point of optimal intervention.
- The modified 2009 criteria listed above appear superior to the traditional HLH-2004 criteria. An autopsy series of patients dying from H1N1 influenza found the modified HLH criteria more likely to be satisfied than HLH-2004 criteria (table below).(26597256, 20008190)
- Determining the H-score might be a preferable approach.(30075527) This is obtained using a calculator 🧮 (units conversion may be needed for triglycerides: 1.5mM = 133 mg/dL; 4mM = 354 mg/dL). The optimal cutoff value is unclear (with potential cutoffs ranging between 138-169).(27298397)
- Some clinicians are moving past rigid criteria, with initiation of therapy before diagnostic criteria are met.(28871523)
- There is no consensus regarding the optimal treatment for infection-induced HLH. Steroid is a mainstay of treatment for HLH and should be given.(21366922, 20348529) Five potential treatment strategies are as follows. The choice of a treatment strategy depends on the certainty of the diagnosis of HLH as well as available medications. Overall, the preferred options might be:
- For possible virus-induced hemophagocytic syndrome: moderate dose of steroids alone.
- For probable/definite virus-induced hemophagocytic syndrome: moderate dose steroid plus a JAK-inhibitor.
- #1: Moderate dose steroids alone
- A moderate dose of steroid may consist of dexamethasone 10 mg/m2 body surface area 🧮 daily (~15-20 mg) or ~125 mg methylprednisolone daily (based on the HLH-2004 protocol).(16937360)
- This might be adequate for early or impending HLH (but not fulminant HLH).
- This steroid dose is essentially identical to that used in the DEXA-ARDS trial (which investigated dexamethasone for the management of ARDS).(32043986) Therefore, this is a reasonable steroid dose for patients in ARDS – even if the diagnosis of HLH is unclear.
- #2: Pulse-dose steroid
- Some case reports describe success from pulse-dose steroid in HLH due to influenza H1N1 (e.g., 500-1,000 mg methylprednisolone daily, for three days).(17106167, 22286408)
- Advantages include that this is inexpensive, readily available, and has a reasonable side-effect profile (particularly at 125 mg IV q6hr, a dose historically used for obstructive lung disease).
- Drawbacks include an increased risk of invasive fungal infection (e.g., aspergillus) and myopathy.
- #3: Moderate dose steroid + Anakinra 📖
- Anakinra is a fairly safe agent that reduces inflammation via inhibition of IL-1 receptors. Re-analysis of a multi-center RCT of septic adults with features of HLH suggested a mortality benefit from Anakinra.(26584195)
- Limitations to this strategy include:
- High cost of anakinra.
- Limited availability of anakinra.
- A requirement for relatively high doses of anakinra, which may be logistically difficult to achieve.
- #4: Moderate dose steroid + JAK inhibitor 📖
- Ruxolitinib is a promising treatment for HLH, which has been validated in some case series.(29417621).
- Baricitinib is supported by less evidence in HLH, but has been demonstrated to improve mortality in patients with COVID pneumonia within the COV-BARRIER trial.(34480861) Tofacitinib has likewise demonstrated benefit among COVID pneumonia.(34133856) In both case, these agents were combined with low-dose corticosteroid among most patients.
- #5: Moderate dose steroid plus Etoposide
- Etoposide is a chemotherapeutic agent, which has been used for pediatric forms of congenital HLH. Case reports describe the successful use of etoposide for influenza-induced HLH.(16530581, 21168053)
- Etoposide's side effect profile isn't as benign as anakinra or JAK inhibitors. However, only one or two doses may be needed to facilitate recovery, with a low cumulative exposure.(21168053) Compared to biologic therapies, etoposide is more widely available and more affordable. It could be a reasonable option if anakinra or JAK-inhibitors were not available.
approach to non-responding patient
definition of non-response?
- This is unclear. Ideally, patients will show some improvement within 2-3 days.(30566567) However, critically ill patients may take longer to recover.
- If the patient improves but then deteriorates, this is a signal that something is amiss.
differential diagnosis may include:
- Virus-associated hemophagocytic syndrome (discussed above).
- Progression of influenza pneumonia into organizing pneumonia.(28810835, 22767562)
- Superimposed bacterial pneumonia (either community- or hospital-acquired).
- Invasive aspergillosis:(30076119, 30577863)
- Can occur even in the context of previously immunocompetent patients (see infographic below).
- Ventilator-induced lung injury with progressive ARDS.
- Influenza-induced myocarditis.
- Superimposed pulmonary embolism (not uncommon in severe influenza with profound inflammation).
- Exacerbation of chronic disease (e.g. COPD, asthma, or heart failure).
- Pleural effusion(s).
- Post-influenza Guillain-Barre Syndrome.
evaluation may include:
- Repeat infectious workup (e.g. cultures, bronchoscopy).
- Evaluation for invasive aspergillus (e.g., serum beta-D-glucan). 📖
- Echocardiogram to evaluate for myocarditis or underlying heart failure.
- Bedside ultrasonography to exclude pleural effusion.
- CT chest with contrast to evaluate for PE or other pulmonary complications.
- Hemophagocytic lymphohistiocytosis labs (ferritin, liver function tests, fibrinogen, triglyceride level).
Numerous complications are possible. These can occur in patients who don't have severe respiratory failure due to their influenza.
- Myocarditis, myopericarditis.
- Myocardial infarction.
- Arrhythmia (especially atrioventricular conduction block and ventricular fibrillation).(31585475)
- Pericardial effusion, tamponade.
neurologic & muscular complications
- Encephalitis (usually within first week, due to virus & cytokines).
- Guillain-Barre syndrome or transverse myelitis (later on, due to immune response).
- Myopathy, rhabdomyolysis.
- Acute kidney injury.
- Acute tubular necrosis.
- Hemolytic uremic syndrome.
virology of influenza
basic properties of influenza
- Influenza is an enveloped, segmented, negative-strand RNA virus.
- The envelope includes three proteins: Hemagglutinin (HA), neuraminidase (NA), and a proton channel (M2).
- Hemagglutinin (HA) binds to sialic acid on host cells. The development of neutralizing antibodies against hemagglutinin correlates with protection following infection or vaccination. Hemagglutinin tends to bind to alpha-2,6-linked sialic acid (mostly located in the upper respiratory tract) and/or alpha-2,3-linked sialic acid (more predominantly located in the lower respiratory tract). Binding to alpha-2,6-linked sialic acid might correlate with disease transmission, whereas binding to alpha-2,3-linked sialic acid might correlate with more severe pneumonia.
- Neuraminidase (NA) is required to release new virions from an infected cell, by cleaving off sialic acid residues from the host cell. This is the target for many anti-influenza medications (neuraminidase inhibitors).
- Proton channel (M2) is required to enter the host cell. Amantadine inhibits this channel, providing it with activity against some strains of influenza A.
- The virus produces its own RNA polymerase which has a high error rate, facilitating rapid mutations. The genetic material of the virus is stored in eight separate segments, which allows for facile reassortment between different viral strains (if two strains cause simultaneous infection).
influenza A vs. influenza B
- Influenza A infects humans and animals (especially birds). Passage of the virus within animals may allow it to gradually accumulate numerous mutations, prior to re-emerging into the human population. This is termed “antigenic shift” because it may lead to a rapid shift in influenza immunology within the human population (causing epidemics and pandemics).
- Influenza B only infects humans. Without an animal reservoir within which to gradually accumulate mutations, it is unable to achieve rapid structural changes. This prevents influenza B from being able to cause pandemics.
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questions & discussion
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- Avoid high-volume resuscitation if at all possible. Fluid isn't the answer for severe influenza.
- Don't miss post-flu pneumonia. Simply because the patient has PCR-positive influenza doesn't necessarily exclude the presence of a concomitant bacterial pneumonia.
- Have a high index of suspicion for MRSA pneumonia among patients with post-flu pneumonia.
- Among ICU patients who aren't responding well to therapy, consider unusual entities such as influenza-induced hemophagocytic lymphohistiocytosis and influenza-induced organizing pneumonia. These diseases are highly treatable if diagnosed promptly.
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- = Link to supplemental media.
- CDC resources on influenza
- Influenza (Chris Nickson, LITFL)
- Naproxen/oseltamavir/clarithromycin triple therapy (PulmCrit)
- Understanding sepsis-HLH overlap syndrome (PulmCrit)
- 11847511 Ninomiya K, Fukui T, Imai T, Matsui M, Matsuoka K. Effect of maclorides on duration and resolution of symptoms and complication of pneumonia in children with influenza. J Nippon Med Sch. 2002 Feb;69(1):53-7. doi: 10.1272/jnms.69.53 [PubMed]
- 16530581 Henter JI, Chow CB, Leung CW, Lau YL. Cytotoxic therapy for severe avian influenza A (H5N1) infection. Lancet. 2006 Mar 11;367(9513):870-3. doi: 10.1016/S0140-6736(06)68232-9 [PubMed]
- 16785288 Mou SS, Nakagawa TA, Riemer EC, McLean TW, Hines MH, Shetty AK. Hemophagocytic lymphohistiocytosis complicating influenza A infection. Pediatrics. 2006 Jul;118(1):e216-9. doi: 10.1542/peds.2005-1861 [PubMed]
- 16937360 Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31. doi: 10.1002/pbc.21039 [PubMed]
- 17106167 Ando M, Miyazaki E, Hiroshige S, Ashihara Y, Okubo T, Ueo M, Fukami T, Sugisaki K, Tsuda T, Ohishi K, Yoshitake S, Noguchi T, Kumamoto T. Virus associated hemophagocytic syndrome accompanied by acute respiratory failure caused by influenza A (H3N2). Intern Med. 2006;45(20):1183-6. doi: 10.2169/internalmedicine.45.1736 [PubMed]
- 18719064 Wunderink RG, Mendelson MH, Somero MS, Fabian TC, May AK, Bhattacharyya H, Leeper KV Jr, Solomkin JS. Early microbiological response to linezolid vs vancomycin in ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus. Chest. 2008 Dec;134(6):1200-1207. doi: 10.1378/chest.08-0011 [PubMed]
- 20008190 Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program. 2009:127-31. doi: 10.1182/asheducation-2009.1.127 [PubMed]
- 20040578 Yamaya M, Shinya K, Hatachi Y, Kubo H, Asada M, Yasuda H, Nishimura H, Nagatomi R. Clarithromycin inhibits type a seasonal influenza virus infection in human airway epithelial cells. J Pharmacol Exp Ther. 2010 Apr;333(1):81-90. doi: 10.1124/jpet.109.162149. [PubMed]
- 20348529 Zheng Y, Yang Y, Zhao W, Wang H. Novel swine-origin influenza A (H1N1) virus-associated hemophagocytic syndrome–a first case report. Am J Trop Med Hyg. 2010 Apr;82(4):743-5. doi: 10.4269/ajtmh.2010.09-0666 [PubMed]
- 20551263 Harms PW, Schmidt LA, Smith LB, Newton DW, Pletneva MA, Walters LL, Tomlins SA, Fisher-Hubbard A, Napolitano LM, Park PK, Blaivas M, Fantone J, Myers JL, Jentzen JM. Autopsy findings in eight patients with fatal H1N1 influenza. Am J Clin Pathol. 2010 Jul;134(1):27-35. doi: 10.1309/AJCP35KOZSAVNQZW [PubMed]
- 21107529 Martin-Loeches I, Lisboa T, Rhodes A, Moreno RP, Silva E, Sprung C, Chiche JD, Barahona D, Villabon M, Balasini C, Pearse RM, Matos R, Rello J; ESICM H1N1 Registry Contributors. Use of early corticosteroid therapy on ICU admission in patients affected by severe pandemic (H1N1)v influenza A infection. Intensive Care Med. 2011 Feb;37(2):272-83. doi: 10.1007/s00134-010-2078-z [PubMed]
- 21163725 Pletz MW, Burkhardt O, Welte T. Nosocomial methicillin-resistant Staphylococcus aureus (MRSA) pneumonia: linezolid or vancomycin? – Comparison of pharmacology and clinical efficacy. Eur J Med Res. 2010 Nov 30;15(12):507-13. doi: 10.1186/2047-783x-15-12-507 [PubMed]
- 21168053 Henter JI, Palmkvist-Kaijser K, Holzgraefe B, Bryceson YT, Palmér K. Cytotoxic therapy for severe swine flu A/H1N1. Lancet. 2010 Dec 18;376(9758):2116. doi: 10.1016/S0140-6736(10)61345-1 [PubMed]
- 21366922 Beutel G, Wiesner O, Eder M, Hafer C, Schneider AS, Kielstein JT, Kühn C, Heim A, Ganzenmüller T, Kreipe HH, Haverich A, Tecklenburg A, Ganser A, Welte T, Hoeper MM. Virus-associated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection. Crit Care. 2011;15(2):R80. doi: 10.1186/cc10073 [PubMed]
- 21471082 Brun-Buisson C, Richard JC, Mercat A, Thiébaut AC, Brochard L; REVA-SRLF A/H1N1v 2009 Registry Group. Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome. Am J Respir Crit Care Med. 2011 May 1;183(9):1200-6. doi: 10.1164/rccm.201101-0135OC [PubMed]
- 21559246 Zhang XY, Ye XW, Feng DX, Han J, Li D, Zhang C. Hemophagocytic Lymphohistiocytosis Induced by Severe Pandemic Influenza A (H1N1) 2009 Virus Infection: A Case Report. Case Rep Med. 2011;2011:951910. doi: 10.1155/2011/951910 [PubMed]
- 21593048 Sundar KM, Thaut P, Nielsen DB, Alward WT, Pearce MJ. Clinical course of ICU patients with severe pandemic 2009 influenza A (H1N1) pneumonia: single center experience with proning and pressure release ventilation. J Intensive Care Med. 2012 May-Jun;27(3):184-90. doi: 10.1177/0885066610396168 [PubMed]
- 21722406 Willekens C, Cornelius A, Guerry MJ, Wacrenier A, Fourrier F. Fulminant hemophagocytic lymphohistiocytosis induced by pandemic A (H1N1) influenza: a case report. J Med Case Rep. 2011 Jul 3;5:280. doi: 10.1186/1752-1947-5-280 [PubMed]
- 21724431 Lai S, Merritt BY, Chen L, Zhou X, Green LK. Hemophagocytic lymphohistiocytosis associated with influenza A (H1N1) infection in a patient with chronic lymphocytic leukemia: an autopsy case report and review of the literature. Ann Diagn Pathol. 2012 Dec;16(6):477-84. doi: 10.1016/j.anndiagpath.2011.03.009 [PubMed]
- 21810744 Han K, Ma H, An X, Su Y, Chen J, Lian Z, Zhao J, Zhu BP, Fontaine RE, Feng Z, Zeng G. Early use of glucocorticoids was a risk factor for critical disease and death from pH1N1 infection. Clin Infect Dis. 2011 Aug;53(4):326-33. doi: 10.1093/cid/cir398 [PubMed]
- 22247123 Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ, Baruch A, McGee WT, Reisman A, Chastre J. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis. 2012 Mar 1;54(5):621-9. doi: 10.1093/cid/cir895 [PubMed]
- 22286408 Asai N, Ohkuni Y, Matsunuma R, Iwama K, Otsuka Y, Kawamura Y, Motojima S, Kaneko N. A case of novel swine influenza A (H1N1) pneumonia complicated with virus-associated hemophagocytic syndrome. J Infect Chemother. 2012 Oct;18(5):771-4. doi: 10.1007/s10156-011-0366-3 [PubMed]
- 22767562 Cornejo R, Llanos O, Fernández C, Carlos Díaz J, Cardemil G, Salguero J, Luengo C, Tobar E, Romero C, Gálvez LR. Organizing pneumonia in patients with severe respiratory failure due to novel A (H1N1) influenza. BMJ Case Rep. 2010 Jul 21;2010:bcr0220102708. doi: 10.1136/bcr.02.2010.2708 [PubMed]
- 23459490 Lejal N, Tarus B, Bouguyon E, Chenavas S, Bertho N, Delmas B, Ruigrok RW, Di Primo C, Slama-Schwok A. Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus. Antimicrob Agents Chemother. 2013 May;57(5):2231-42. doi: 10.1128/AAC.02335-12 [PubMed]
- 23568605 Jiang H, Tang RN, Wang J. Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: meta-analysis of randomised controlled trials. Eur J Clin Microbiol Infect Dis. 2013 Sep;32(9):1121-8. doi: 10.1007/s10096-013-1867-z [PubMed]
- 24238896 Chavanet P. The ZEPHyR study: a randomized comparison of linezolid and vancomycin for MRSA pneumonia. Med Mal Infect. 2013 Dec;43(11-12):451-5. doi: 10.1016/j.medmal.2013.09.011 [PubMed]
- 24420846 Caffrey AR, Morrill HJ, Puzniak LA, Laplante KL. Comparative effectiveness of linezolid and vancomycin among a national veterans affairs cohort with methicillin-resistant Staphylococcus aureus pneumonia. Pharmacotherapy. 2014 May;34(5):473-80. doi: 10.1002/phar.1390 [PubMed]
- 24916853 Peyrani P, Wiemken TL, Kelley R, Zervos MJ, Kett DH, File TM Jr, Stein GE, Ford KD, Scerpella EG, Welch V, Ramirez JA; IMPACT-HAP Study Group. Higher clinical success in patients with ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus treated with linezolid compared with vancomycin: results from the IMPACT-HAP study. Crit Care. 2014 Jun 10;18(3):R118. doi: 10.1186/cc13914 [PubMed]
- 25066668 Niederman MS, Chastre J, Solem CT, Wan Y, Gao X, Myers DE, Haider S, Li JZ, Stephens JM. Health economic evaluation of patients treated for nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus: secondary analysis of a multicenter randomized clinical trial of vancomycin and linezolid. Clin Ther. 2014 Sep 1;36(9):1233-1243.e1. doi: 10.1016/j.clinthera.2014.06.029 [PubMed]
- 25169846 Higashi F, Kubo H, Yasuda H, Nukiwa T, Yamaya M. Additional treatment with clarithromycin reduces fever duration in patients with influenza. Respir Investig. 2014 Sep;52(5):302-9. doi: 10.1016/j.resinv.2014.05.001. [PubMed]
- 25355172. Wang Y, Zou Y, Xie J, Wang T, Zheng X, He H, Dong W, Xing J, Dong Y. Linezolid versus vancomycin for the treatment of suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a systematic review employing meta-analysis. Eur J Clin Pharmacol. 2015 Jan;71(1):107-15. doi: 10.1007/s00228-014-1775-x [PubMed]
- 26382940 Reveles KR, Mortensen EM, Attridge RT, Frei CR. Comparative-effectiveness of vancomycin and linezolid as part of guideline-recommended empiric therapy for healthcare-associated pneumonia. BMC Res Notes. 2015 Sep 17;8:450. doi: 10.1186/s13104-015-1396-1 [PubMed]
- 26584195 Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, Cron RQ, Opal SM. Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial. Crit Care Med. 2016 Feb;44(2):275-81. doi: 10.1097/CCM.0000000000001402 [PubMed]
- 26597256 Schulert GS, Zhang M, Fall N, Husami A, Kissell D, Hanosh A, Zhang K, Davis K, Jentzen JM, Napolitano L, Siddiqui J, Smith LB, Harms PW, Grom AA, Cron RQ. Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza. J Infect Dis. 2016 Apr 1;213(7):1180-8. doi: 10.1093/infdis/jiv550 [PubMed]
- 27208687 Tong MC, Wisniewski CS, Wolf B, Bosso JA. Comparison of Linezolid and Vancomycin for Methicillin-Resistant Staphylococcus aureus Pneumonia: Institutional Implications. Pharmacotherapy. 2016 Jul;36(7):731-9. doi: 10.1002/phar.1771 [PubMed]
- 27298397 Debaugnies F, Mahadeb B, Ferster A, Meuleman N, Rozen L, Demulder A, Corazza F. Performances of the H-Score for Diagnosis of Hemophagocytic Lymphohistiocytosis in Adult and Pediatric Patients. Am J Clin Pathol. 2016 Jun;145(6):862-70. doi: 10.1093/ajcp/aqw076 [PubMed]
- 27836900 Woods PS, Doolittle LM, Rosas LE, Joseph LM, Calomeni EP, Davis IC. Lethal H1N1 influenza A virus infection alters the murine alveolar type II cell surfactant lipidome. Am J Physiol Lung Cell Mol Physiol. 2016 Dec 1;311(6):L1160-L1169. doi: 10.1152/ajplung.00339.2016. [PubMed]
- 27884765 Hung IFN, To KKW, Chan JFW, Cheng VCC, Liu KSH, Tam A, Chan TC, Zhang AJ, Li P, Wong TL, Zhang R, Cheung MKS, Leung W, Lau JYN, Fok M, Chen H, Chan KH, Yuen KY. Efficacy of Clarithromycin-Naproxen-Oseltamivir Combination in the Treatment of Patients Hospitalized for Influenza A(H3N2) Infection: An Open-label Randomized, Controlled, Phase IIb/III Trial. Chest. 2017 May;151(5):1069-1080. doi: 10.1016/j.chest.2016.11.012 [PubMed]
- 28159162 Li H, Cao B. Pandemic and Avian Influenza A Viruses in Humans: Epidemiology, Virology, Clinical Characteristics, and Treatment Strategy. Clin Chest Med. 2017 Mar;38(1):59-70. doi: 10.1016/j.ccm.2016.11.005 [PubMed]
- 28631531 Wohlfarth P, Agis H, Gualdoni GA, Weber J, Staudinger T, Schellongowski P, Robak O. Interleukin 1 Receptor Antagonist Anakinra, Intravenous Immunoglobulin, and Corticosteroids in the Management of Critically Ill Adult Patients With Hemophagocytic Lymphohistiocytosis. J Intensive Care Med. 2019 Sep;34(9):723-731. doi: 10.1177/0885066617711386 [PubMed]
- 28810835 Asai N, Yokoi T, Nishiyama N, Koizumi Y, Sakanashi D, Kato H, Hagihara M, Suematsu H, Yamagishi Y, Mikamo H. Secondary organizing pneumonia following viral pneumonia caused by severe influenza B: a case report and literature reviews. BMC Infect Dis. 2017 Aug 15;17(1):572. doi: 10.1186/s12879-017-2677-1 [PubMed]
- 28871523 Kumar B, Aleem S, Saleh H, Petts J, Ballas ZK. A Personalized Diagnostic and Treatment Approach for Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Adults. J Clin Immunol. 2017 Oct;37(7):638-643. doi: 10.1007/s10875-017-0439-x. [PubMed]
- 29417621 Zandvakili I, Conboy CB, Ayed AO, Cathcart-Rake EJ, Tefferi A. Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: A second experience. Am J Hematol. 2018 May;93(5):E123-E125. doi: 10.1002/ajh.25063 [PubMed]
- 30075527 Merrill SA, Naik R, Streiff MB, Shanbhag S, Lanzkron S, Braunstein EM, Moliterno AM, Brodsky RA. A prospective quality improvement initiative in adult hemophagocytic lymphohistiocytosis to improve testing and a framework to facilitate trigger identification and mitigate hemorrhage from retrospective analysis. Medicine (Baltimore). 2018 Aug;97(31):e11579. doi: 10.1097/MD.0000000000011579 [PubMed]
- 30076119. Schauwvlieghe AFAD, Rijnders BJA, Philips N, Verwijs R, Vanderbeke L, Van Tienen C, Lagrou K, Verweij PE, Van de Veerdonk FL, Gommers D, Spronk P, Bergmans DCJJ, Hoedemaekers A, Andrinopoulou ER, van den Berg CHSB, Juffermans NP, Hodiamont CJ, Vonk AG, Depuydt P, Boelens J, Wauters J; Dutch-Belgian Mycosis study group. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir Med. 2018 Oct;6(10):782-792. doi: 10.1016/S2213-2600(18)30274-1. [PubMed]
- 30140503 Küçük MP, Öztürk ÇE, İlkaya NK, Eyüpoğlu S, Ülger F, Şahinoğlu AH. Management of Acute Respiratory Distress Syndrome with H1N1 Influenza Virus in Pregnancy: Successful Mechanical Ventilation and Weaning with Airway Pressure Release Ventilation. Turk J Anaesthesiol Reanim. 2018 Feb;46(1):62-65. doi: 10.5152/TJAR.2017.33044 [PubMed]
- 30172033 Wieruszewski PM, Linn DD. Contemporary management of severe influenza disease in the intensive care unit. J Crit Care. 2018 Dec;48:48-55. doi: 10.1016/j.jcrc.2018.08.015 [PubMed]
- 30184455 Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, Ishida T, Sekino H, Yamada K, Portsmouth S, Kawaguchi K, Shishido T, Arai M, Tsuchiya K, Uehara T, Watanabe A; Baloxavir Marboxil Investigators Group. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018 Sep 6;379(10):913-923. doi: 10.1056/NEJMoa1716197 [PubMed]
- 30566567 Uyeki TM, Bernstein HH, Bradley JS, Englund JA, File TM, Fry AM, Gravenstein S, Hayden FG, Harper SA, Hirshon JM, Ison MG, Johnston BL, Knight SL, McGeer A, Riley LE, Wolfe CR, Alexander PE, Pavia AT. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa. Clin Infect Dis. 2019 Mar 5;68(6):e1-e47. doi: 10.1093/cid/ciy866. [PubMed]
- 30577863. Winiszewski H, Rougny AC, Lagoutte-Renosi J, Millon L, Capellier G, Navellou JC, Piton G, Clairet AL. The pharmacokinetic challenge of treating invasive aspergillosis complicating severe influenzae assisted by extracorporeal membrane oxygenation. Crit Care. 2018 Dec 22;22(1):355. doi: 10.1186/s13054-018-2285-5. [PubMed]
- 31189475 Chow EJ, Doyle JD, Uyeki TM. Influenza virus-related critical illness: prevention, diagnosis, treatment. Crit Care. 2019 Jun 12;23(1):214. doi: 10.1186/s13054-019-2491-9 [PubMed]
- 31313681 Sarda C, Palma P, Rello J. Severe influenza: overview in critically ill patients. Curr Opin Crit Care. 2019 Oct;25(5):449-457. doi: 10.1097/MCC.0000000000000638. [PubMed]
- 31585475 Cantan B, Luyt CE, Martin-Loeches I. Influenza Infections and Emergent Viral Infections in Intensive Care Unit. Semin Respir Crit Care Med. 2019 Aug;40(4):488-497. doi: 10.1055/s-0039-1693497 [PubMed]
- 31912206 Torres A, Loeches IM, Sligl W, Lee N. Severe flu management: a point of view. Intensive Care Med. 2020 Feb;46(2):153-162. doi: 10.1007/s00134-019-05868-8 [PubMed]
- 32068576 O'Sullivan S, Torres A, Rodriguez A, Martin-Loeches I. Influenza management with new therapies. Curr Opin Pulm Med. 2020 May;26(3):215-221. doi: 10.1097/MCP.0000000000000667 [PubMed]
- 32572532 Verweij PE, Rijnders BJA, Brüggemann RJM, Azoulay E, Bassetti M, Blot S, Calandra T, Clancy CJ, Cornely OA, Chiller T, Depuydt P, Giacobbe DR, Janssen NAF, Kullberg BJ, Lagrou K, Lass-Flörl C, Lewis RE, Liu PW, Lortholary O, Maertens J, Martin-Loeches I, Nguyen MH, Patterson TF, Rogers TR, Schouten JA, Spriet I, Vanderbeke L, Wauters J, van de Veerdonk FL. Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion. Intensive Care Med. 2020 Aug;46(8):1524-1535. doi: 10.1007/s00134-020-06091-6 [PubMed]
- 34133856 Guimarães PO, Quirk D, Furtado RH, Maia LN, Saraiva JF, Antunes MO, Kalil Filho R, Junior VM, Soeiro AM, Tognon AP, Veiga VC, Martins PA, Moia DDF, Sampaio BS, Assis SRL, Soares RVP, Piano LPA, Castilho K, Momesso RGRAP, Monfardini F, Guimarães HP, Ponce de Leon D, Dulcine M, Pinheiro MRT, Gunay LM, Deuring JJ, Rizzo LV, Koncz T, Berwanger O; STOP-COVID Trial Investigators. Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021 Jul 29;385(5):406-415. doi: 10.1056/NEJMoa2101643 [PubMed]
- 34480861 Marconi VC, Ramanan AV, de Bono S, Kartman CE, Krishnan V, Liao R, Piruzeli MLB, Goldman JD, Alatorre-Alexander J, de Cassia Pellegrini R, Estrada V, Som M, Cardoso A, Chakladar S, Crowe B, Reis P, Zhang X, Adams DH, Ely EW; COV-BARRIER Study Group. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021 Aug 31:S2213-2600(21)00331-3. doi: 10.1016/S2213-2600(21)00331-3 [PubMed]