The Shift Change · Case 004

The Cough That Wasn't Flu

Three weeks of cough in the middle of flu season. A negative rapid flu test, two rounds of antibiotics, and now she is septic on high-flow oxygen. She is also on a biologic for rheumatoid arthritis. What is your first order, and who needs a mask?

Apex Clinical Group · November 3, 2026

ICUInfectious DiseaseTuberculosisRheumatology

The case

A 57-year-old woman with rheumatoid arthritis comes to the ED with three weeks of cough, fevers, and drenching night sweats. She has lost about 13 pounds without trying. Her rheumatoid arthritis was diagnosed two years ago: inflammatory synovitis in both hands, rheumatoid factor negative, anti-CCP strongly positive. Because methotrexate alone was not controlling it, her rheumatologist added adalimumab, an anti-TNF biologic, five months ago. Her screening IGRA before the biologic was negative.

Two weeks ago, at urgent care, a rapid influenza antigen test was negative. She was told it was "probably a virus" and sent home with azithromycin. When the cough kept going, a second clinic gave her levofloxacin. She felt a little better for a few days, then worse. Her husband says she has been "sweating through the sheets." She grew up in the Philippines and moved to Texas twenty years ago.

  • General: ill-appearing, diaphoretic, speaking in short sentences
  • Lungs: coarse crackles in the right upper field; diffuse fine crackles elsewhere
  • Monitor: temperature 102.7 °F, heart rate 122, blood pressure 92/54, respiratory rate 30, SpO2 86% on room air
  • Labs: lactate 3.1, WBC 13.8, sodium 129, creatinine 1.3, albumin 2.6, AST/ALT mildly elevated
  • Chest X-ray: a cavity in the right upper lobe, plus innumerable tiny nodules scattered through both lungs

She goes to the ICU on high-flow nasal cannula. She is in a shared ED bay with a surgical mask on her face and the curtain pulled.

She is septic, it is flu season, and she is immunosuppressed. What do you order in the first hour, and what precaution goes up right now? Commit to an answer, then work the questions.

Clinic = urgent care, two weeks before admission. HFNC = high-flow nasal cannula.

ClinicEDICU day 3
Temp (°F)100.6102.7100.4
Heart rate9812296
BP124/7692/54112/66
Resp. rate203022
SpO296% room air86% room air94% HFNC
Lactate—3.11.4
Rapid fluNegative——
Flu PCR—SentNegative
Sputum AFB—SentPositive

Questions

Q1 First hour. What do you order, and what goes up on the door?

Two things happen at once, and neither waits for the other.

Treat the sepsis like sepsis.

  • Draw blood cultures, then give broad-spectrum antibiotics per protocol. Do not hold them for imaging or sputum.
  • Check lactate, give IV crystalloid for the hypoperfusion, and reassess. Start a vasopressor per protocol if her pressure does not hold.
  • Send an influenza PCR (NAAT) and start oseltamivir now. She is hospitalized and severely ill in flu season. Treatment should not wait for the result, and a negative rapid antigen test two weeks ago does not rule flu out. Adjust oseltamivir for her renal function.
  • Hold the methotrexate and the adalimumab. A biologic is not continued through an active, serious infection.

Put her in airborne isolation right now. An upper-lobe cavity, three weeks of cough, night sweats, weight loss, birth in a high-incidence country, and an anti-TNF drug add up to contagious pulmonary tuberculosis until proven otherwise. That means an airborne infection isolation room (negative pressure, door closed), and a fit-tested N95 respirator for every staff member who enters. A surgical mask on the patient is for transport, not a substitute. Droplet precautions for flu are not enough for TB. Airborne precautions cover both.

Call infection prevention as soon as you suspect it, and report it. Suspected TB is reportable: in Texas, notify the local health department within one working day of suspicion, without waiting for confirmation (check your own state’s rules). Infection prevention identifies the staff and patients exposed in the shared ED bay, and the health department leads the contact investigation.

Q2 Her IGRA before the biologic was negative. Why is TB still at the top of the list?

Because the IGRA cannot carry that much weight.

  • IGRA and TST detect TB infection, not disease. A positive result cannot tell latent from active TB, and a negative result does not rule active TB out.
  • Immunosuppression lowers their sensitivity. Both tests depend on the patient's T cells responding. She was already on methotrexate when she was screened, so a false negative is possible.
  • A negative screen is a snapshot. It cannot account for a later exposure.

Then look at the drug. TNF holds TB granulomas together, so blocking it can let a contained infection break out (see the section below). TB on anti-TNF therapy often shows up within the first year of treatment, earliest with infliximab and somewhat later with adalimumab, and it is more often disseminated or extrapulmonary. Her chest X-ray has both: a cavity and a miliary pattern.

And the levofloxacin was a trap. Fluoroquinolones have activity against M. tuberculosis. A course can partly treat TB, make the patient feel briefly better, delay the diagnosis, and select for fluoroquinolone resistance. When TB is on the list, avoid a fluoroquinolone as empiric "pneumonia" coverage until TB has been worked up.

Q3 How do you prove it?

Do not lean on another IGRA. It will not answer the question in front of you. Go to the source.

  • Sputum for AFB smear and mycobacterial culture, collected per your facility's TB protocol (typically three specimens), with a nucleic acid amplification test (NAAT) on at least one. NAAT is fast, and some assays (such as Xpert MTB/RIF) also detect rifampin-resistance mutations. A negative NAAT does not exclude TB, especially when the smear is negative.
  • Culture is the gold standard. It confirms the diagnosis and gives drug susceptibilities, but it takes weeks. Send it even when the smear and NAAT are positive.
  • If she cannot cough up sputum, consider induced sputum or bronchoscopy, done in the isolation room with airborne precautions. Both generate aerosols.
  • With a miliary pattern, send mycobacterial blood cultures and think about other sites: the liver, the bone marrow, and the CNS if she becomes confused or develops headache.
  • Test for HIV. Every patient with TB gets an HIV test, and it changes treatment.
  • Check hepatitis B and C serologies before TB drugs start. Hepatitis B is common in the Philippines, and her liver enzymes are already up.

Do not wait for results to treat. She is critically ill with a miliary pattern and a high probability of TB, so once the specimens are collected, start four-drug therapy empirically with infectious disease.

Meanwhile, her blood cultures and influenza PCR are also pending. Whatever returns, the decision point on the empiric coverage is 48 to 72 hours.

Q4 Smear positive, NAAT positive for TB with no rifampin resistance detected. Flu PCR and blood cultures are negative. What changes now?

Continue four-drug therapy: RIPE (rifampin, isoniazid, pyrazinamide, ethambutol), per protocol and with infectious disease and public health. Treatment is given by directly observed therapy (DOT), coordinated with the health department, so every dose is taken. Multiple drugs prevent resistance. Never treat active TB with a single drug.

Know the toxicities you will be watching:

  • Liver: isoniazid, rifampin, and pyrazinamide can all cause hepatitis. Get baseline liver tests and trend them. Her recent methotrexate is one more reason.
  • Eyes: ethambutol can cause optic neuritis. Check baseline visual acuity and red-green color vision, and ask about vision changes at each visit.
  • Nerves: isoniazid can cause peripheral neuropathy. Give pyridoxine (vitamin B6) to patients at risk.
  • Interactions: rifampin is a strong enzyme inducer. It lowers the levels of many drugs, including warfarin, many anticoagulants and antiretrovirals, steroids, and hormonal contraception. Pharmacy should review the whole medication list.

Clean up the rest (stewardship):

  • Flu PCR negative and TB explains the illness: stop oseltamivir. (In a hospitalized patient with lower respiratory disease and no other explanation, a negative nasal test does not fully exclude flu; test a lower respiratory specimen before stopping.)
  • Blood cultures negative at 48 to 72 hours and no other bacterial source: stop the broad-spectrum antibiotics. Do not leave duplicate coverage running "just in case."
  • Document the indication and the planned duration for everything she stays on.

She stays in airborne isolation until she is no longer infectious: on effective multidrug therapy (commonly at least 2 weeks), clinically improving, and with three consecutive negative AFB sputum smears collected 8 to 24 hours apart, at least one early in the morning. Infection prevention and the health department make the final call.

Q5 Her rheumatologist asks: when can she restart her rheumatoid arthritis medicines?

Not yet, and not alone. Rheumatology and infectious disease decide this together, after TB treatment is well established and she is clearly improving. There is no "restart on day X" rule. Note the lesson for every patient starting a biologic: screen for TB and hepatitis B and C at baseline, and treat latent TB before starting when it is found.

Two rheumatology pearls hide in her history:

  • Her RF was negative, and she still has rheumatoid arthritis. A negative rheumatoid factor (RF) does not rule out rheumatoid arthritis, and a positive one does not prove it. Anti-CCP is more specific. Her strongly positive anti-CCP with inflammatory synovitis fits the diagnosis.
  • Test for a reason. Serologies help when the history and exam already point to a disease. A positive ANA or RF in a low-risk patient misleads more often than it helps.
★ The reveal

All three sputum smears were AFB-positive, and the NAAT detected M. tuberculosis complex with no rifampin-resistance mutation. CT showed the right upper lobe cavity with diffuse miliary nodules. Influenza PCR, blood cultures, and HIV were negative. Weeks later, the culture grew pan-susceptible M. tuberculosis.

She had been started on RIPE with pyridoxine as soon as specimens were collected; once results returned, oseltamivir and the broad-spectrum antibiotics were stopped. Her fever broke over the first week, she came off high flow on day 5, and she left the ICU on day 7, still in airborne isolation. The health department began contact tracing (her household, the urgent care, and the shared ED bay) and arranged directly observed therapy. Adalimumab and methotrexate stayed on hold.

The rapid flu test was negative from the start. What sent her home twice was the assumption that a cough in flu season is the flu.

Why anti-TNF drugs wake up tuberculosis

Most people infected with M. tuberculosis never get sick. Their immune system builds a wall around the bacteria and keeps them there, sometimes for decades. That wall is the granuloma, and TNF is one of the main signals that keeps it standing.

What TNF does. Tumor necrosis factor-alpha activates macrophages so they can kill the mycobacteria they swallow. It also recruits immune cells and holds them together in an organized granuloma around the infection. The bacteria stay alive inside, but walled in.

What blocking it does. Anti-TNF drugs are very good at turning down the inflammation that destroys joints in rheumatoid arthritis. They do the same thing in the granuloma: macrophages kill less well, the structure loosens, and bacteria that were contained escape. Latent infection becomes active disease.

Why it looks different. Reactivation on anti-TNF therapy often comes within the first year, earliest with infliximab, and it is more often extrapulmonary or disseminated, including miliary TB, than ordinary reactivation. The usual signs can be blunted by the drug, and fever can be the main clue.

Not every biologic carries the same risk. The risk has been reported higher with the monoclonal antibodies (infliximab, adalimumab) than with etanercept. Every biologic still requires baseline TB screening.

Bedside takeaway: fever, cough, and weight loss in a patient on a biologic is TB until proven otherwise. Isolate first, then send sputum for smear, NAAT, and culture. A negative screening IGRA does not end the conversation.

Teaching points

  1. A negative rapid flu test does not rule out influenza. Molecular testing (NAAT/PCR) is preferred. Start an antiviral promptly for hospitalized or severely ill patients without waiting for results, and consider stopping it if the PCR is negative and another diagnosis explains the illness. In lower respiratory disease, a negative nasal test does not fully exclude flu.
  2. Antibiotics do not treat influenza. Give them for a suspected bacterial infection, not for a cough in flu season.
  3. Suspected pulmonary TB means airborne isolation now: a negative-pressure room and a fit-tested N95 for staff. Droplet precautions are not enough.
  4. Suspected TB is reportable. Call the health department on suspicion, not confirmation. They lead contact tracing and directly observed therapy.
  5. IGRA and TST cannot tell latent from active TB, and immunosuppression can make them falsely negative. Diagnose active TB with sputum AFB smear, NAAT, and culture.
  6. Avoid fluoroquinolones as empiric pneumonia coverage when TB is possible. They can mask TB and breed resistance.
  7. Active TB is never treated with one drug. RIPE to start; monitor the liver (INH, rifampin, PZA), vision (ethambutol), and nerves (INH, give pyridoxine), and review every drug against rifampin's interactions.
  8. Stewardship is part of the save. Cultures before antibiotics when feasible, then reassess at 48 to 72 hours. Narrow or stop, and document the duration.
  9. Before any biologic, screen for TB and hepatitis B and C. Hold biologics during serious active infection.
  10. Anti-CCP is more specific for rheumatoid arthritis than rheumatoid factor. A negative rheumatoid factor does not exclude rheumatoid arthritis.

Who does what

Physician / APP

Names TB as a possibility at the first look and orders airborne isolation, runs the sepsis bundle and empiric antivirals in parallel, holds the biologic, orders sputum smear, NAAT, and culture, starts RIPE with ID, and de-escalates at 48 to 72 hours.

RN

Moves her to a negative-pressure room and checks it is working, wears a fit-tested N95, collects sputum per protocol, gets baseline vision and liver labs drawn, watches for hepatitis and vision changes, and teaches the family what isolation means.

RT

Runs high-flow oxygen inside the isolation room, treats induced sputum and bronchoscopy as aerosol-generating, wears an N95 for every entry, and watches the work of breathing for the next step up.

Medic / flight

Chronic cough, night sweats, and weight loss on an immunosuppressant: N95 on the crew, a surgical mask on the patient, ventilation on in the box, and the receiving facility told before arrival so an isolation room is ready.

References

  • Lewinsohn, D. M., Leonard, M. K., LoBue, P. A., Cohn, D. L., Daley, C. L., Desmond, E., Keane, J., Lewinsohn, D. A., Loeffler, A. M., Mazurek, G. H., O’Brien, R. J., Pai, M., Richeldi, L., Salfinger, M., Shinnick, T. M., Sterling, T. R., Warshauer, D. M., & Woods, G. L. (2017). Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: Diagnosis of tuberculosis in adults and children. Clinical Infectious Diseases, 64(2), 111–115. https://doi.org/10.1093/cid/ciw778
  • Nahid, P., Dorman, S. E., Alipanah, N., Barry, P. M., Brozek, J. L., Cattamanchi, A., Chaisson, L. H., Chaisson, R. E., Daley, C. L., Grzemska, M., Higashi, J. M., Ho, C. S., Hopewell, P. C., Keshavjee, S. A., Lienhardt, C., Menzies, R., Merrifield, C., Narita, M., O'Brien, R., . . . Vernon, A. (2016). Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: Treatment of drug-susceptible tuberculosis. Clinical Infectious Diseases, 63(7), e147–e195. https://doi.org/10.1093/cid/ciw376
  • Keane, J., Gershon, S., Wise, R. P., Mirabile-Levens, E., Kasznica, J., Schwieterman, W. D., Siegel, J. N., & Braun, M. M. (2001). Tuberculosis associated with infliximab, a tumor necrosis factor α–neutralizing agent. New England Journal of Medicine, 345(15), 1098–1104. https://doi.org/10.1056/NEJMoa011110
  • Uyeki, T. M., Bernstein, H. H., Bradley, J. S., Englund, J. A., File, T. M., Fry, A. M., Gravenstein, S., Hayden, F. G., Harper, S. A., Hirshon, J. M., Ison, M. G., Johnston, B. L., Knight, S. L., McGeer, A., Riley, L. E., Wolfe, C. R., Alexander, P. E., & Pavia, A. T. (2019). Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clinical Infectious Diseases, 68(6), e1–e47. https://doi.org/10.1093/cid/ciy866
  • Jensen, P. A., Lambert, L. A., Iademarco, M. F., & Ridzon, R. (2005). Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Recommendations and Reports, 54(RR-17), 1–141. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5417a1.htm
  • Evans, L., Rhodes, A., Alhazzani, W., Antonelli, M., Coopersmith, C. M., French, C., Machado, F. R., Mcintyre, L., Ostermann, M., Prescott, H. C., Schorr, C., Simpson, S., Wiersinga, W. J., Alshamsi, F., Angus, D. C., Arabi, Y., Azevedo, L., Beale, R., Beilman, G., . . . Levy, M. (2021). Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock 2021. Critical Care Medicine, 49(11), e1063–e1143. https://doi.org/10.1097/CCM.0000000000005337
  • Singh, J. A., Saag, K. G., Bridges, S. L., Jr., Akl, E. A., Bannuru, R. R., Sullivan, M. C., Vaysbrot, E., McNaughton, C., Osani, M., Shmerling, R. H., Curtis, J. R., Furst, D. E., Parks, D., Kavanaugh, A., O’Dell, J., King, C., Leong, A., Matteson, E. L., Schousboe, J. T., . . . McAlindon, T. (2016). 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care & Research, 68(1), 1–25. https://doi.org/10.1002/acr.22783
  • Fraenkel, L., Bathon, J. M., England, B. R., St. Clair, E. W., Arayssi, T., Carandang, K., Deane, K. D., Genovese, M., Huston, K. K., Kerr, G., Kremer, J., Nakamura, M. C., Russell, L. A., Singh, J. A., Smith, B. J., Sparks, J. A., Venkatachalam, S., Weinblatt, M. E., Al-Gibbawi, M., . . . Akl, E. A. (2021). 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care & Research, 73(7), 924–939. https://doi.org/10.1002/acr.24596

Card image: representative chest X-ray of miliary tuberculosis, not this patient, cropped. From “Miliary tuberculosis presenting with hyponatremia and ARDS in an 82-year-old immunocompetent female,” by B. Herreros, I. Plaza, R. García, M. Chichón, C. Guerrero, and E. Pintor, 2018, Pathogens, 7(3), Article 72 (https://doi.org/10.3390/pathogens7030072), via Wikimedia Commons. CC BY 4.0.

Educational content only, not medical advice. Cases are drawn from clinical experience; details are changed so no patient can be identified. Medications are named without doses; follow your facility's protocols and your local medical direction.

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